Steroid treatment with glucocorticoid drugs such as dexamethasone, prednisolone, hydrocortisone, etc. can lead to drug dependence, that is, an adaptive state formed after long-term administration. Drug dependence may cause withdrawal syndrome after stopping the drug abruptly.
Glucocorticoids are used to treat inflammatory, allergic, immune and malignant diseases. In the insufficiency of the adrenal cortex, the dose of glucocorticoid should mimic the physiological concentration and circadian rhythm of cortisol secretion to compensate for the inadequate production of natural cortisol. Even in the case of relatively low exposure to glucocorticoid therapy, long-term excessive replacement can lead to weight gain, glucose intolerance and abnormal bone metabolism, which can lead to osteoporosis.
In various conditions such as congenital adrenal hyperplasia, polycystic ovary syndrome and certain types of tumors, the body may produce too much androgens, male hormones. Such patients may not show signs of glucocorticoid deficiency. Women may experience symptoms such as hirsutism, oligomenorrhea, acne, infertility, and male pattern baldness. Men are usually asymptomatic, but acne, early baldness, and testicular adrenal gland resting tumors may occur. In this case, the use of glucocorticoids is prescribed to suppress excessive androgen production, rather than to compensate for the lack of cortisol. Here, the prescribed glucocorticoid acts in the following way through the hypothalamic-pituitary-adrenal (HPA) axis feedback loop: increased glucocorticoids suppress the release of adrenocorticotropic hormone (ACTH), thereby inhibiting the biosynthesis of pregnenolone from cholesterol. Pregnenolone is a steroid and the precursor of all other steroids, including glucocorticoids, mineralocorticoids, androgens and estrogens. Therefore, glucocorticoid drugs suppress excessive androgen production, but at a cost of suppressing all other steroid hormones as well.
The type of glucocorticoid drug prescribed depends on whether the goal is to compensate cortisol insufficiency or to suppress excessive androgen production. Hydrocortisone suppresses HPA least and dexamethasone most, with prednisolone in the middle.
When glucocorticoids are used in doses exceeding equivalent physiological production by a healthy organism, and the glucocorticoid treatment is suddenly stopped, HPA suppression prevents the adrenal glands from producing enough cortisol. Even lower but close to physiological doses of glucocorticoid drugs for long time may cause problems. Over a period of several weeks to several months or years, this may result in the gradual atrophy of cortisol producing cells in the adrenal glands, unable to respond to ACTH stimulation the HPA axis, leading to secondary adrenal insufficiency, i.e. the inability to produce normal levels of cortisol. Therefore, glucocorticoid withdrawal must not happen suddenly. Generally, patients taking glucocorticoid doses for less than two weeks are less likely to develop HPA axis suppression, and can stop treatment suddenly without gradual reduction, except patients receiving frequent "short-term" steroid therapy, such as in asthma.
In the case of chronic treatment that has been carried out for months or years, the goal is to gradually reduce the therapeutic dose to a physiological level, such as by reducing the dose step-by-step every 3-4 days for a few weeks, and then slowly withdrawing the drug for several months, to restore the HPA axis. Importantly, the adrenal suppression effect may last for a period of time, so after stopping glucocorticoid treatment, it may take more than a year for the HPA axis to fully recover.
- Paragliola RM, Papi G, Pontecorvi A, Corsello SM. Treatment with
Synthetic Glucocorticoids and the Hypothalamus-Pituitary-Adrenal
Axis. Int J Mol Sci. 2017 Oct 20;18(10):2201. doi:
10.3390/ijms18102201. PMID: 29053578; PMCID: PMC5666882
- Nicolaides NC, Pavlaki AN, Maria Alexandra MA, Chrousos GP. Glucocorticoid Therapy and Adrenal Suppression. 2018 Oct 19. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland HJ, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP, editors. Endotext Internet. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 25905379