Cushing’s syndrome is a syndrome with clinical manifestations of centripetal obesity, hypertension, hypokalemia, and osteoporosis caused by endogenous cortisol increase. The cause can be pituitary tumors or ectopic neuroendocrine tumors that secrete excessive adrenocorticotropic hormone (ACTH) stimulating the adrenal glands to secrete cortisol, or adrenal tumors or hyperplasia that autonomously secrete excessive cortisol, the former being called ACTH-dependent Cushing’s syndrome and the latter ACTH-independent Cushing’s syndrome. The preferred treatment is surgery, but in clinical practice, there is difficulty in locating and diagnosing ACTH-dependent Cushing’s syndrome, and some patients cannot undergo surgery, while those who undergo surgery have a therapeutic remission rate of 80% to 90%. In order to alleviate the damage to the body caused by hypercortisolism, pharmacotherapy, as a second-line treatment, is also an essential treatment for patients who cannot undergo surgery in the short term or cannot The present paper introduces the relevant pharmacological treatments and their research progresses that are currently applied in clinical practice.
In view of the fact that Cushing’s syndrome is a difficult disease, there are few types of related drugs, although some drugs have been used for a long time, they still continue to be used because of their efficacy, while the new drugs developed in recent years for the treatment of Cushing’s syndrome need more clinical validation. Drugs for the treatment of hypercortisolism are usually divided into three categories according to the site of action: (1) drugs that act specifically on pituitary adenomas to inhibit ACTH secretion; (2) drugs that act on adrenal tumors to inhibit cortisol synthesis; and (3) antagonists that act on glucocorticoid receptors in peripheral target organs, such as mifepristone, to alleviate the clinical manifestations of hypercortisolism by blocking the peripheral effects of cortisol.
1 Drugs acting on the pituitary gland to inhibit ACTH secretion
1.1 Somatostatinreceptor agonist
Growth inhibitory receptor agonists are also known as growth inhibitory analogs. It has been found that the pituitary ACTH adenoma in Cushing’s disease expresses abundant growth inhibitory receptors (somatostatinreceptor, sstr), especially sstr5. Among the synthetic growth inhibitory analogs, octreotide mainly binds to sstr2, so it has limited effect on the treatment of Cushing’s disease. Pasireotide not only binds to multiple growth inhibitor receptor subtypes (sstr1, 2, 3 and 5), but its functional activity (based on EC50 values) in sstr1, sstr3 and sstr5 is 30, 11 and 158 times higher than that of octreotide, respectively. It also inhibits CRH-stimulated ACTH secretion via sstr5 in in vitro assays. Currently, pareotide is the only growth inhibitor analogue that has been validated in phase III clinical trials for the treatment of Cushing’s disease. A 6-month multicenter randomized double-blind phase III trial, SOM230B2305, included 162 patients with Cushing’s disease who were randomly assigned to either the 600 μg or 900 μg group of pareotide, and urinary free cortisol (UFC) decreased by an average of 50% after 2 months of treatment and remained stable until The patients’ urinary free cortisol (UFC) decreased by 50% on average after 2 months of treatment and remained stable until the end of the trial. The UFC returned to normal in 25.6% of patients in the 600 μg group and 26.3% of patients in the 900 μg group. The most common adverse reactions during treatment were elevated blood glucose, with 72.8% of patients experiencing hyperglycemia-related adverse reactions, followed by gastrointestinal reactions such as diarrhea (58%) and nausea (52%), and gallbladder stones in 30% of patients. The US Food and Drug Administration (FDA) approved Signifor for the treatment of Cushing’s disease that cannot be treated surgically.
In addition, there are reports suggesting the use of growth inhibitor analogs for the treatment of ectopic ACTH-secreting neuroendocrine tumors, particularly in patients with positive growth inhibitor receptor imaging results.
1.2 Dopamine receptor agonists
Dopamine receptor 2 (D2) is also abundantly expressed on the surface of pituitary ACTH adenomas, and the dopamine receptor agonist cabergoline is commonly used to treat prolactinomas (PRL), but ACTH levels can also be decreased if bromocriptine or cabergoline is applied to patients with Cushing’s disease. After applying cabergoline 1 to 3 mg/week to 20 patients with Cushing’s disease, a significant decrease in UFC was observed in 60% of the patients, with 40% of them having a decrease in UFC to normal, and the degree of response to this drug correlated with the expression of D2 receptors. For ectopic ACTH syndrome, good therapeutic effects of D2 receptor agonists have also been reported. For example, in three patients with unremitting ectopic ACTH syndrome after surgery, the UFC was completely normalized in two patients after 3 months with the application of cabergoline 3.5 mg per week, but one of them showed escape.
Given that both sstr and D2 are abundantly expressed on neuroendocrine tumors, the combined application of growth inhibitory analogs and D2 agonists could theoretically improve the therapeutic effect, and in vitro studies have shown that for growth hormone tumors, BIM-23A760 (a combined sstr and D2 agonist) showed better results compared to sstr agonist or D2 agonist alone.
1.3 PPARγ agonists
The study in 2002 first demonstrated that peroxisome proliferator-activated receptor γ (PPARγ) was expressed not only in liver and adipose tissue, but also in hypothalamus, pituitary and adrenal tissue, in addition to pituitary ACTH adenoma tissue. High concentrations of PPARγ receptor agonists such as rosiglitazone [150 mg/(kg・d)] were shown in in vitro tests to inhibit the proliferation of AtT20 tumor cells in mice cultured in vitro, and in 75% of the mice with tumor implantation, hypercortisolism did not develop, and also reduced ACTH levels by 75% and cortisol levels by 96%. ambrosi et al. studied 14 patients with Cushing’s disease (18-68 years) with rosiglitazone 8 mg/d and after 30-60 d of treatment, ACTH levels and blood cortisol levels decreased in 6 patients, while UFC levels returned to normal [(1238±211) versus (154±40) nmol/24h, P=0.03], but 8 patients did not show efficacy. Immunohistochemistry showed no difference in the expression of PPARγ in pituitary adenoma tissue at about 50% in both patients who responded and did not respond to rosiglitazone. This discrepancy in the results of in vivo and in vitro studies limits the further use of PPARγ agonists and therefore is not widely used.
1.4 Cyproheptadine
Cyproheptadine is a serotonin receptor antagonist at a daily dose of 24 mg that effectively inhibits the secretion of ACTH and cortisol in patients with Cushing’s disease. This effect can last for several months and can be reversed after discontinuation, but no subsequent studies have shown similar efficacy, and the efficacy of this drug in treating patients with Cushing’s disease is controversial.
1.5 Sodium valproate (valproicacid)
Sodium valproate is a gamma-aminobutyric acid (GABA) reuptake inhibitor that inhibits CRH secretion by increasing GABA in in vitro tests. However, its efficacy in patients with Cushing’s disease is not good, but several reports suggest that sodium valproate is effective in patients with Nelson syndrome and pituitary macroadenomas, decreasing ACTH secretion and reducing tumor volume, but is not associated with inhibition of CRH secretion, as the latter two are pituitary-derived ACTH-dependent Cushing’s disease in which CRH is inhibited, presumably possibly related to valproic acid sodium’s tumor The direct inhibitory effect of valproate may be relevant.
2 Drugs acting on adrenal glands to inhibit cortisol secretion
2.1 Imidazole derivatives
Imidazole derivatives, such as ketoconazole and fluconazole, inhibit cytochrome P450-dependent enzymes such as 17α hydroxylase, 11β hydroxylase and cholesterol side chain cleavage enzymes in murine adrenal cortical cells. Ketoconazole and fluconazole are often used in clinical practice for fungal infections, but if applied at 200-600 mg/d, ketoconazole becomes an inhibitor of gonadal and adrenal steroid synthesis. Reports suggest that long-term treatment with ketoconazole in patients with Cushing’s syndrome can lead to sustained reduction in UFC levels and improvement in clinical symptoms of hypercortisolism. Like ketoconazole, fluconazole is an antifungal imidazole derivative, and doses of 200-400 mg/d are also effective in suppressing cortisol secretion in cases of adrenocortical carcinoma. However, fluconazole was less effective than ketoconazole in an in vitro cultured mouse adrenocortical carcinoma cell line. This class of drugs can be used as a preferred preoperative preparation for the next step in the treatment of patients with severe hypercortisolism such as transsphenoidal surgery, and patients with severe hypercortisolism such as metastatic adrenocortical carcinoma or ectopic ACTH syndrome require higher doses of up to 1200 mg/d. When administering ketoconazole, dose adjustments are required to maintain cortisol levels in the normal range to avoid adrenocortical insufficiency. Toxic adverse reactions are dose-dependent and the most common ones are nausea, vomiting, abdominal pain and pruritus. Hepatotoxicity may also occur and liver function needs to be monitored frequently during treatment and discontinuation should be considered when transaminases are elevated more than 3 times the upper limit of normal. Theoretically, the efficacy is similar for all types of Cushing’s syndrome, but early reports suggest that ketoconazole has a longer duration of efficacy in patients with ACTH non-dependent Cushing’s syndrome.
2.2 Aminoglutethimide
Aminoglutethimide inhibits the conversion of cholesterol to pregnenolone by inhibiting cholesterol side chain cleavage enzymes, thus inhibiting the synthesis of cortisol, aldosterone and androgens. Dosage ranges from 500 to 2000 mg/d. A gradual decrease in cortisol levels may be observed after dosing, and glucocorticoid replacement therapy may eventually be required. In patients with ACTH-dependent Cushing’s syndrome, aminoglucagon may transiently inhibit cortisol synthesis, but this effect is often reversed by stimulation with ACTH. In a large series of studies on Cushing’s syndrome, aminoguidanoic treatment resulted in a 62% remission rate in 21 patients with adrenocortical carcinoma; a 100% remission rate in 5 patients with adrenal adenoma; and a 42% remission rate in 33 patients with Cushing’s disease. Adverse effects of aminoglutethimide include gastrointestinal reactions such as anorexia, nausea, vomiting and neurological symptoms such as malaise, drowsiness and blurred vision. Because aminoglutethimide acts at the first steps of steroid synthesis, it is more effective in adrenocortical carcinomas that may secrete multiple hormones such as cortisol, aldosterone, and androgens simultaneously. Unfortunately, since 2007, the manufacturer has stopped producing these drugs, so they are no longer used in China and abroad.
2.3 Metyrapone
Metyrapone, also known as metyrapone, is an 11β hydroxylase inhibitor. Metyrapone was initially used for the differential diagnosis of Cushing’s syndrome and later also for the treatment of hypercortisolism. The dose is 4.5g/d, inhibition occurs within hours, and the maintenance dose is 500-2000mg/d. Early reports suggest significant improvement in clinical symptoms after 21 months of mepyrone treatment in 13 patients with Cushing’s disease. It can be used in individual cases in patients with metastatic adrenocortical carcinoma and inoperable ectopic ACTH syndrome. The adverse effects are nausea, vomiting and vertigo, which may be associated with a sudden drop in cortisol levels. In patients with Cushing’s disease there are specific adverse effects of acne and hirsutism due to increased ACTH levels resulting from blocked steroid hormone synthesis, which stimulates increased androgen bypass synthesis. In patients with Cushing’s disease, the inhibition of 11β hydroxylase activity leads to elevated levels of 11 deoxycorticosterone, causing hypertension and hypokalemia.
2.4 Mitotane (mitotane)
Mitotane, also known as o,p-DDD, has the longest history of use among oral cytotoxic drugs and has been shown to selectively inhibit adrenocorticotropic hormone synthesis in both human and animal studies. It is converted to acyl chloride by P450-mediated hydroxylation and covalent binding to specific biologic nucleophiles (bionucleophiles), and can also be involved in oxidative damage by lipid peroxidation through the generation of free radicals by peroxidation. The activity of mitotane varies in different species, with the strongest effect in dogs and moderate effect in humans.
Mitotane is commonly used in the treatment of functional and non-functional adrenocortical carcinomas, but at low doses it can also be used to treat Cushing’s disease by inhibiting adrenocortical hormone synthesis. In addition, the combination of mitotane with radiation therapy has been reported to result in clinical and biochemical remission in 80% of patients with Cushing’s disease. It has a dose-dependent adverse effect, usually at a maximum dose of 6 g/d, with some patients with adrenocortical carcinoma tolerating higher doses for short periods of time. This drug is lipoprotein dependent for absorption and transport, so it is best used with lipid-containing foods. Efficacy is monitored by measuring UFC. Serum cortisol is elevated during treatment because mitotane increases the binding of cortisol to CBG. At low doses (2-4 g/d), mitotane rarely affects aldosterone synthesis; whereas, at high doses, replacement therapy with 9α fludrocortisone may be required. Early adverse reactions include anorexia, nausea, and drowsiness; adverse reactions can be reversed by discontinuing the drug for several days, and reintroduction of the drug can be started at small doses. Rare adverse reactions are maculopapular rash and exfoliative dermatitis. Hepatotoxicity requires discontinuation of the drug if it occurs because of potential teratogenicity and the need for contraception during use.
2.5 Etomidate
Etomidate as a muscle relaxant anesthetic, etomidate can cause acute adrenocortical insufficiency and increase mortality in critically ill patients. In healthy subjects, etomidate dose-dependently blocks the stimulatory effect of exogenous ACTH on cortisol synthesis, suggesting that it inhibits 11β hydroxylase activity, thereby reducing blood cortisol and aldosterone concentrations, but increases blood ACTH levels, 11 deoxycortisol, and deoxycorticosterone levels.1 In a patient with severe Cushing’s syndrome with ectopic ACTH syndrome, continuous intravenous infusion of etomidate effectively In a child with severe Cushing’s syndrome, intravenous etomidate (3.0 mg/h) reduced serum cortisol from 1250 nmol/L to 250 nmol/L within 24 h. The combination of etomidate and hydrocortisone maintained stable cortisol levels for up to 12 d. Overall, etomidate is only indicated for short-term use in critically ill patients with co-morbidities prior to further treatment. In general, etomidate should only be used for a short period of time before proceeding to the next treatment in patients with severe complications.
2.6 Trilostane
Trilostane is a competitive inhibitor of cholesterol synthase 3-beta hydroxysteroid dehydrogenase, which blocks the conversion of pregnenolone to progesterone, ultimately reducing the synthesis of cortisol, aldosterone and androstenedione. trilostane reduced steroid levels in 7 patients with Cushing’s disease, with a 50% reduction in serum cortisol and 17-hydroxysteroids and a 70% reduction in UFC, but an increase in dehydroepiandrosterone levels, as well as an improvement in Blood pressure and blood glucose were also improved. However, another study suggested that cortisol levels did not decrease in five patients treated with trovatriptan (1440 mg/d). Therefore, its therapeutic effect is still controversial.
3 Glucocorticoid receptor antagonists
The only glucocorticoid receptor antagonist available is mifepristone, a progesterone receptor and type II glucocorticoid receptor antagonist with three times the affinity for glucocorticoids and 10 times the affinity for endogenous cortisol than dexamethasone. More studies have confirmed the efficacy of mifepristone in chronic and recurrent Cushing’s disease, and it has also been used in the palliative treatment of ectopic ACTH syndrome and cortisol-secreting adrenocortical carcinoma. Mifepristone is highly protein-bound, with a mean half-life of 85 h for multiple doses and takes approximately 2 weeks to clear from the circulation after discontinuation. The recommended maximum dose is 1200 mg/d, but for patients with severe renal insufficiency (creatinine clearance <30 mL/min) or mild to moderate hepatic insufficiency, the maximum dose is 600 mg/d. The SEISMIC trial evaluated mifepristone in 50 patients with Cushing's syndrome (43 Cushing's disease, 4 ectopic ACTH syndrome, and 3 adrenocortical carcinomas). The effectiveness and safety of mifepristone were evaluated in 50 patients with Cushing's syndrome (43 Cushing's disease, 4 ectopic ACTH syndrome, and 3 adrenocortical carcinoma). The patients showed an 87% improvement in clinical symptoms (P<0.0001< span="">). Compared with baseline, weight loss was 5.7% (P<0.001< span="">), with more than 50% of subjects losing ≥5% of their body weight from baseline; 60% of patients with concomitant glucose abnormalities had a decrease of ≥25% of the area under the glucose curve in oral glucose tolerance tests, glycated hemoglobin decreased from 7.43% at baseline to 6.29% (P<0.001< span="" >), and a decrease in mean diastolic blood pressure of ≥5 mmHg (1 mmHg=0.133 kPa) in 38% of patients with concomitant hypertension (P<0.05< span="">).
On February 17, 2012, the U.S. Food and Drug Administration (FDA) has approved Korlym (mifepristone) for the treatment of adult patients with endogenous Cushing’s syndrome who have combined type 2 diabetes or glucose intolerance and who are not candidates for surgery or for whom surgical treatment is ineffective, at a regular dose of 300 mg, one tablet daily with meals, which may be increased from once daily depending on clinical response and tolerability Depending on clinical response and tolerability, the dose may be increased from 300 mg once daily to a maximum dose of 1200 mg daily, with a once daily dose of no more than 600 mg for patients with renal impairment and mild to moderate hepatic impairment.
In addition to the above drugs, successful treatment of Cushing’s disease with retinoic acid and relief of refractory Cushing’s disease pituitary invasive macroadenoma with temozolomide have also been reported, but they are case reports and therefore not reviewed in this article. In conclusion, among the drugs that inhibit ACTH secretion, sstr agonists and D2 agonists can obtain good efficacy, while PPARγ agonists, cycloheximide and sodium valproate are not widely used because of inconsistency in efficacy. The drugs that inhibit cortisol synthesis are definitely effective and commonly used are ketoconazole and methylprednisolone; mitotane is only approved for patients with adrenocortical carcinoma due to more adverse effects; etomidate is the only intravenous drug that can be used for the rescue treatment of severe Cushing’s disease. Mifepristone, as the only glucocorticoid receptor antagonist, has long-lasting and definite efficacy, but lacks monitoring indicators and the efficacy is mainly evaluated based on clinical symptoms. The action characteristics of various drugs are summarized in Table 2, and clinically appropriate drugs should be selected and individualized according to the patient’s condition.