Steroid Hormones (Glucocorticoids)

About Glucocorticoid Steroid Hormones

Corticosteroids are steroid hormones synthesized in the adrenal cortex. Natural corticosteroids and their synthetic derivatives are used in medicine to treat adrenal insufficiency. Additionally, some of these drugs are used as anti-inflammatories, immunosuppressants, anti-allergics, shock reducers, and other properties in certain medical conditions.

Classification and methods of use of corticosteroids:
The use of corticosteroids as drugs began in the 1940s. In the late 1930s, hormonal compounds of the steroid type were discovered in the adrenal cortex. In 1937, mineralocorticoid dehydrocortisone was isolated from the adrenal cortex, and in the 1940s, cortisone and hydrocortisone were isolated. The wide range of pharmacological effects of hydrocortisone and cortisone helped in their use as drugs. They were subsequently synthesized. Hydrocortisone (cortisol) is the main and most effective corticosteroid synthesized in the human body, and there are other less effective corticosteroids such as cortisone, corticosterone, dehydrocortisol, and dehydrocorticosterone. Adrenal hormones are produced under the control of the central nervous system and are closely related to the function of the pituitary gland. Adrenocorticotropic hormone (ACTH) from the pituitary gland is a physiological stimulant for the adrenal cortex. ACTH increases the synthesis and secretion of corticosteroids. These, in turn, affect the pituitary gland, inhibiting the secretion of ACTH and thus reducing future stimulation of the adrenal cortex (according to the principle of inverse negative feedback). Long-term use of corticosteroids (cortisone and its derivatives) can lead to inhibition and reduction in the size of the adrenal cortex, as well as inhibition of secretion not only of ACTH but also of ovarian and thyroid stimulating hormones from the pituitary gland.

Pathways for regulating the synthesis and secretion of adrenal gland hormones
Cortisone and hydrocortisone were found among the natural corticosteroids that are practically used as drugs. However, cortisone more frequently causes side effects than other corticosteroids, and therefore, with the appearance of currently more effective and safer drugs, its use is limited. In medical practice, natural hydrocortisone or its esters (hydrocortisone acetate and hydrocortisone hemisuccinate) are used. A wide range of synthetic corticosteroids has been manufactured, including non-fluorinated corticosteroids (such as prednisone, prednisolone, and methylprednisolone) and fluorinated ones (such as dexamethasone, betamethasone, triamcinolone, flumethasone, etc.). Generally, these compounds are more active than natural corticosteroids and work at lower doses. Synthetic corticosteroids have a similar effect to natural corticosteroids but have a different ratio of glucocorticoid and mineral activity.

Fluorinated derivatives have a better ratio between glucocorticoid/anti-inflammatory activity and mineral activity.
For example, the anti-inflammatory activity of dexamethasone (compared to hydrocortisone) increases by 30 times, while the activity of betamethasone increases by 25 to 40 times, and the activity of triamcinolone increases by 5 times, with less effect on fluid and salt exchange. Fluorinated derivatives not only have high efficiency but also have low absorption when used topically, thus the likelihood of systemic side effects is lower.
The mechanism of action of corticosteroids at the molecular level has not yet been determined. It is believed that the effect of corticosteroids on target cells is mainly at the level of gene regulation. This is done through the interaction of corticosteroids with their specific intracellular receptors (alpha-isoforms). These nuclear receptors are capable of binding to DNA and belong to a multi-sensitive family of receptors that interact with compounds. Corticosteroid receptors have been found in most cells, but their number varies in different cells, and they can also vary in terms of molecular weight, similarity to the hormone, and other physical and chemical properties. In the absence of the hormone, internal receptors are inactive and consist of groups of proteins in the cytoplasm, including heat shock proteins (Hsp90 and Hsp70), immunophilins with a molecular weight of 56,000, and others. These proteins contribute to maintaining an optimal range of hormone binding to the receptor and ensure strong interaction between the receptor and the hormone.

The Molecular Mechanism of Glucocorticoids Action:
After penetrating the cellular membrane, corticosteroids interact with their receptors inside the cell, leading to the activation of a complex of compounds. In this process, the multi-unit protein complex is dismantled, where heat shock proteins (Hsp90 and Hsp70) and immunophilins dissociate. As a result, the receptor protein, which enters the complex monomerically, gains the ability to translocate towards the nucleus.
Subsequently, the resulting “steroid-receptor” pairs are transported to the nucleus, where they interact with parts of the DNA, located in the promoter region of the steroid-responsive gene – known as glucocorticoid response elements (GRE), and regulate (activate or suppress) the process of transcription for some genes (genomic effect). This leads to the stimulation or inhibition of messenger RNA synthesis and the production of a variety of regulatory proteins and enzymes, which mediate cellular effects.
Recent studies have shown that in addition to GREs, glucocorticoid receptors interact with various transcription factors, such as Activator Protein-1 (AP-1), Nuclear Factor Kappa B (NF-kB), and others. It has also been shown that NF-kB and AP-1 nuclear factors regulate several genes, including cytokine genes, adhesion molecules, proteases, and others, which play a role in immune and inflammatory responses.
Furthermore, another mechanism of glucocorticoid action has been recently discovered, involving its effect on the inhibitory phosphorylation of nuclear factor kappa B (NF-kB) in the cytoplasm – IkBa. However, many effects of glucocorticoids (such as their rapid inhibition of ACTH secretion) occur very quickly and cannot be explained by gene expression (referred to as non-genomic effects). It is believed that such characteristics may be mediated through non-transcriptional mechanisms, or by interacting with glucocorticoid receptors discovered on the cellular membrane of some cells. It is also believed that glucocorticoid effects may be executed at different levels depending on the dose. For example, gene effects occur at low concentrations of glucocorticoids (> 10^-12 mol/liter) (requiring over 30 minutes to develop), while non-genomic effects occur at high concentrations.
Glucocorticoids Effects:
The anti-inflammatory effect of glucocorticoids is attributed to several factors, including inhibition of phospholipase A2 activity. Glucocorticoids act indirectly by increasing the expression of genes encoding lipocortins (annexins), stimulating the production of these proteins, one of which is lipomodulin, which inhibits phospholipase A2 activity. This inhibition leads to the suppression of arachidonic acid release and reduces the formation of inflammatory mediators such as prostaglandins, leukotrienes, thromboxanes, platelet activating factor, and others. Additionally, glucocorticoids reduce the expression of the gene encoding for cyclooxygenase-2 (COX-2) synthesis, thereby suppressing the formation of inflammatory prostaglandins.
Moreover, glucocorticoids improve microcirculation at the site of inflammation, cause vasoconstriction of capillaries, and reduce fluid leakage. Glucocorticoids stabilize cell membranes, including lysosomal membranes, preventing the release of lysosomal enzymes and thereby reducing their concentration at the site of inflammation.
As a result, glucocorticoids affect both alternative and secretory stages of inflammation and prevent the spread of the inflammatory process. They reduce the migration of mononuclear cells to the site of inflammation and inhibit fibrous tissue proliferation, contributing to the resolution of inflammation. They inhibit mucus production, thereby restricting the binding of water and proteins in the plasma at the site of inflammation. They inhibit collagenase activity, preventing the destruction of cartilage and bones in rheumatoid arthritis inflammation.
Antiallergic Effect:
The antiallergic effect involves reducing the synthesis and secretion of allergic mediators, inhibiting the release of histamine and other biologically active compounds from mast cells and basophils, reducing circulating basophils, inhibiting the proliferation of lymphoid and connective tissue, reducing the number of lymphoid and fatty cells, reducing the sensitivity of effector cells to allergic mediators, inhibiting antibody synthesis, and altering the body’s immune response.
The characteristic feature of glucocorticoids is their immunosuppressive activity. Unlike cytostatics, the immunosuppressive properties of glucocorticoids are not related to their antiproliferative effect, but are the result of inhibiting various stages of the immune response – inhibiting the migration of stem cells from the bone marrow and B lymphocytes, inhibiting the activity of T and B lymphocytes, inhibiting the release of cytokines (IL-1, IL-2, and gamma-interferon) from leukocytes and macrophages, as well as reducing the formation and increasing the degradation of complement components, inhibiting Fc receptors for antibodies, and inhibiting the functions of leukocytes and macrophages.
Furthermore, glucocorticoids reduce the production and increase the degradation of cellular inflammatory factors, thereby inhibiting cellular inflammatory responses. Their effect on intracellular calcium concentration may inhibit many inflammatory pathways.
Overall, the multifaceted effects of glucocorticoids on the body demonstrate the complexity of their impact on inflammation and immunity-related biological processes, highlighting their important role in regulating these processes and alleviating associated disorders. These effects encompass genomic actions, involving gene expression regulation through glucocorticoid response elements, as well as non-genomic actions, mediated by interactions with various transcription factors and other cellular components. Additionally, glucocorticoids exert anti-inflammatory effects by inhibiting key enzymes and mediators involved in the inflammatory cascade, stabilizing cell membranes, and modulating microcirculation. Their antiallergic effects involve suppressing allergic mediator synthesis and release, reducing immune cell proliferation and activity, and altering immune response patterns. The immunosuppressive properties of glucocorticoids contribute to their therapeutic efficacy in various conditions, albeit with potential side effects necessitating careful clinical management.

Corticosteroids have anti-shock and anti-toxic properties, including increasing blood pressure by enhancing the circulating catecholamines and restoring adrenergic sensitivity to catecholamines, as well as causing vasoconstriction. They also activate liver enzymes involved in metabolism and detoxification.

Corticosteroids significantly affect all types of metabolism: carbohydrates, proteins, fats, and minerals. Carbohydrate metabolism is influenced by promoting gluconeogenesis in the liver, increasing blood glucose levels (potentially leading to glucosuria), and facilitating glycogen storage in the liver. Protein metabolism is affected by inhibiting protein synthesis and accelerating protein breakdown, particularly in the skin, muscles, and bones, leading to muscle weakness, skin and muscle atrophy, and delayed wound healing. These compounds also redistribute fat, increasing fat breakdown in peripheral tissues and primarily accumulating fat in the face (moon face), shoulders, and abdomen.

Corticosteroids possess mineralocorticoid activity, causing sodium and water retention in the body by increasing their absorption in the renal tubules and stimulating potassium excretion. This effect is more pronounced with natural corticosteroids like cortisol and hydrocortisone and less so with semi-synthetic corticosteroids like prednisone, prednisolone, and methylprednisolone. Fludrocortisone exhibits greater mineralocorticoid activity, while fluorinated corticosteroids like triamcinolone, dexamethasone, and betamethasone have minimal mineralocorticoid activity.

Additionally, corticosteroids reduce calcium absorption in the intestines and promote its excretion from bones and kidneys, potentially leading to hypocalcemia, increased urinary calcium excretion, and the development of corticosteroid-induced osteoporosis.

Following a single dose of corticosteroids, changes in blood parameters are observed, such as decreased lymphocytes, monocytes, eosinophils, and basophils in peripheral blood, along with a rise in segmented neutrophils and an increase in red blood cell count.

Long-term use of corticosteroids suppresses the function of the hypothalamic-pituitary-adrenal axis.

Corticosteroids vary in their activity and pharmacokinetic parameters such as absorption rate, half-life, and others, as well as in their modes of administration.

Corticosteroid drugs that affect the adrenal glands are classified into several groups.
In terms of origin:

  • Natural: Such as hydrocortisone and cortisone.
  • Synthetic: Such as prednisolone, methylprednisolone, prednisone, triamcinolone, dexamethasone, and betamethasone.
    In terms of duration of action:
  • Short-acting steroids (Half-life 8-12 hours): Hydrocortisone, cortisone.
  • Intermediate-acting steroids (Half-life 18-36 hours): Prednisolone, prednisone, methylprednisolone.
  • Long-acting steroids (Half-life 36-54 hours): Triamcinolone, dexamethasone, betamethasone.
    The duration of action of corticosteroid drugs depends on the method and site of administration, the solubility of the drug formulation, and the dosage given.

Corticosteroid therapy can be divided into three types: Replacement therapy, Suppressive therapy, and Pharmacodynamic therapy.

  • Replacement therapy with corticosteroids is necessary in cases of adrenal insufficiency. In this type of treatment, physiological doses of corticosteroids are used, and during stressful situations (such as surgery, injury, or acute illness), doses are increased by 2-5 times. The daily rhythmic secretion of corticosteroids should be considered: the largest dose (or the entire dose) is given in the morning (6-8 am). In cases of chronic adrenal insufficiency (Addison’s disease), corticosteroids can be used lifelong.
  • Suppressive therapy with corticosteroids is used in congenital adrenal hyperplasia – a disorder in the adrenal gland function in children. In this type of treatment, corticosteroids are used at pharmacological doses (above physiological levels), leading to the suppression of adrenocorticotropic hormone secretion by the pituitary gland, and thus reducing the excess androgen secretion from the adrenal gland. The largest dose (2/3) is given before bedtime to prevent peak secretion of adrenocorticotropic hormone.
  • Pharmacodynamic therapy with corticosteroids is more commonly used, including the treatment of inflammatory and allergic diseases. Pharmacodynamic therapy can be divided into several types: Immediate therapy, Restricted therapy, and Long-term therapy. Immediate therapy is used in acute life-threatening emergencies, where corticosteroids are administered intravenously, starting with large doses (5 mg/kg/day); after the patient exits the acute state (1-2 days), corticosteroids are immediately discontinued.

Effective corticosteroid therapy requires the use of high doses to treat acute life-threatening emergencies. Corticosteroids are administered intravenously at high doses, usually starting at a rate of 5 mg/kg of body weight per day. After the patient’s condition stabilizes, the dose is gradually reduced until the physician can determine the necessary therapeutic dose to maintain therapeutic benefit with the least risk of side effects.

Restricted corticosteroid therapy involves using lower doses than required for effective treatment, providing corticosteroids at doses sufficient to control symptoms without causing effects similar to effective treatment. This type of therapy aims to reduce the dose and minimize the side effects resulting from corticosteroid use.

Long-term corticosteroid therapy involves using low doses for an extended period. This type of treatment is common in chronic autoimmune and inflammatory diseases, aiming to maintain permanent symptom control and reduce disease deterioration without exposing the patient to the severe side effects of prolonged corticosteroid use.

Corticosteroid therapy should be administered under the supervision and guidance of a specialist physician, and the patient should be regularly monitored to ensure that the treatment achieves the desired benefit without serious side effects.

These different scenarios for intermittent corticosteroid administration help reduce the inhibitory effect on the hypothalamic-pituitary-adrenal axis.

  • Alternating therapy involves using short- or medium-acting corticosteroids (such as prednisolone or methylprednisolone) in single doses in the morning every 48 hours.
  • Intermittent regimen involves using corticosteroids for short periods over 3-4 days with rest periods of 4 days between cycles.
  • Pulse therapy involves administering large doses of the drug rapidly intravenously (not less than 1 g), often used for emergency treatment. Methylprednisolone is often chosen for this purpose due to its better distribution in inflamed tissues and fewer side effects.
    Long-term drug therapy is used to treat diseases with continuous progression. Corticosteroids are given orally at doses exceeding physiological doses, and treatment lasts for several years. In this case, corticosteroids are withdrawn very slowly.

The type of treatment can be changed during therapy, depending on the response to treatment and the nature of the disease.

For the side effects of glucocorticoids:

  • Cushing’s syndrome (delayed sodium and water excretion in the body with the possibility of edema, potassium loss, and high blood pressure)
  • Hyperglycemia and cortisone diabetes
  • Slowed tissue regeneration processes
  • Exacerbation of gastric and intestinal ulcers
  • Pancreatitis due to bleeding
  • Decreased body resistance to infections
  • Increased blood clotting with a risk of thrombosis
  • Appearance of acne, moon face, feminine facial features, obesity, menstrual irregularities, and others

Regarding the side effects of glucocorticoids, glucocorticoids should only be used in the presence of clear indications and under careful medical supervision. The contraindications for the use of glucocorticoids are relative. In emergency cases, hypersensitivity is the only contraindication for regular short-term glucocorticoid use. In other cases, contraindications should be considered when planning long-term treatment.

Glucocorticoids are prohibited in cases such as severe hypertension, Cushing’s syndrome, pregnancy (where fetal adrenal gland development may be inhibited), stage III circulatory failure, acute myocarditis, psychosis, nephritis, osteoporosis, peptic ulcer, recent surgeries, gonorrhea, active tuberculosis (if specific treatment is not available), diabetes, and allergy to glucocorticoids (including in medical history). Regular use of glucocorticoids in children is only possible in absolute necessity cases (delayed growth may occur).

Preparations containing glucocorticoids (such as ointments and drops) should not be used in cases of viral eye and skin diseases, as they inhibit regeneration processes, leading to the formation of widespread ulcers (in ophthalmic practice up to corneal hernia). In cases of fungal and parasitic skin diseases, ointments containing glucocorticoids should be avoided if antifungal or insecticidal drugs are not added.

Regarding drug interactions:

  • Glucocorticoids decrease the effectiveness of microsomal liver enzymes and increase the effects of estrogens and oral contraceptives.
  • Glucocorticoids increase the likelihood of electrolyte disturbances and potassium depletion with thiazide diuretics, urinary excretion drugs, and anticoagulants.
  • Alcohol consumption and nonsteroidal anti-inflammatory drugs increase the risk of ulcers and bleeding in the gastrointestinal tract.
  • Immunosuppressants increase the risk of infection.
  • Glucocorticoids reduce the effectiveness of anti-diabetic drugs, insulin, diuretics, anticoagulants, lisinopril and indandiones, heparin, streptokinase, urokinase, and decrease the concentration of salicylates and mexiletine in the blood.
  • Taking prednisolone and paracetamol increases the risk of liver toxicity.

According to the European classification (Niedner, Schopf, 1993), topical steroids are divided into 4 categories based on their potential efficacy:

  1. Weak category (class I) – includes hydrocortisone at a concentration of 0.1–1%, prednisolone at a concentration of 0.5%, fluocinolone acetonide at a concentration of 0.0025%.
  2. Moderate potency category (class II) – includes alclometasone at a concentration of 0.05%, betamethasone valerate at a concentration of 0.025%, triamcinolone acetonide at concentrations of 0.02% and 0.05%, fluocinolone acetonide at concentrations of 0.00625% and others.
  3. Strong category (class III) – includes betamethasone valerate at a concentration of 0.1%, betamethasone dipropionate at concentrations of 0.025% and 0.05%, hydrocortisone butyrate at a concentration of 0.1%, methylprednisolone acetate at a concentration of 0.1%, mometasone furoate at a concentration of 0.1%, triamcinolone acetonide at concentrations of 0.025% and 0.1%, fluticasone at a concentration of 0.05%, fluocinolone acetonide at a concentration of 0.025% and others.
  4. Very strong category (class IV) – includes clobetasol propionate at a concentration of 0.05% and others.