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Changes in the Canine Plasma Lipidome after Short- and Long-Term Excess Glucocorticoid Exposure

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Uses, Types, Side Effects, and Risks

Glucocorticoids are powerful medicines that fight inflammation and work with your immune system to treat wide range of health problems.

Your body actually makes its own glucocorticoids. These hormones have many jobs, such as controlling how your cells use sugar and fat and curbing inflammation. Sometimes, though, they aren’t enough. That’s when the man-made versions can help.

How They Work

Inflammation is your immune system’s response to an injury or infection. It makes your body produce more white blood cells and chemicals to help you heal. Sometimes, though, that response is too strong and can even be dangerous. Asthma, for example, is inflammation in your airways that can keep you from breathing.

If you have an autoimmune disease, your body triggers inflammation by mistake. That means your immune system attacks healthy cells and tissue as if they were viruses or bacteria.

Glucocorticoids keep your body from pumping out so many of the chemicals involved in inflammation. They can also dial back your immune system’s response by changing the way white blood cells work.

Conditions They Treat

Glucocorticoids treat many conditions that are caused by inflammation, such as:

Doctors also prescribe glucocorticoids for people who get organ transplants. After the procedure, your immune system sees the new organ as an invader and attacks it. Drugs that turn down your immune system, such as glucocorticoids, can keep your body from rejecting the new organ.

Types of Glucocorticoids

A glucocorticoid is a kind of steroid. The type you need depends on the specific health condition you have.

Among the most common ones are:

Side Effects

How glucocorticoids affect you will depend on the specific drug or the dose you take. For example, if you only take one every so often for flare-ups of joint inflammation, you may not have any side effects.

Common problems include:

What Are the Risks?

It’s usually safe for most people to take glucocorticoids for a little while. But using them for a long time can cause health problems, including:

If you notice any changes in how you feel while you take these drugs, be sure to tell your doctor.

If you’re pregnant or breastfeeding, talk with your doctor about the risks and benefits of prednisone and other glucocorticoids. These medications may be a slight risk to your baby. However, if you’re taking them because you have a serious health problem or a life-threatening disease, staying on your treatment may outweigh the chance that the drugs will harm your baby.

Tell your doctor if you have any of these medical problems before you start taking a glucocorticoid:

No Excess Risk of Breast Cancer among Female Users of Systemic Glucocorticoids

• Breast cancer
• Clinical endocrinology
• Hormonal carcinogenesis

Introduction

Recently published evidence suggests that hyperinsulinemia, insulin-like growth factors, and abnormal glucose intolerance may promote mammary carcinogenesis (1-6) and that women with type 2 diabetes are at increased risk for postmenopausal breast cancer (1, 3). Insulin and insulin-like growth factors are major determinants of proliferation and apoptosis (5, 6). Steroid hormones are also important in the etiology of breast cancer: both estrogens and androgens are dominant hormones in breast cancer development (7). Glucocorticoids are immunosuppressive steroid hormones widely used in the treatment of allergic and autoimmune diseases. Metabolic changes, including decreased glucose tolerance, are well-known side effects of glucocorticoids (8). Because these drugs are commonly used and breast cancer is fairly common, any relation between the two would have major public health implications. Therefore, we examined the risk of breast cancer in a large cohort of female glucocorticoids users.

Materials and Methods

We used the population-based Prescription Database of North Jutland County, Denmark (9) (500,000 inhabitants) to identify the study cohort (Table 1). This database is generated by a computerized pharmacy accounting system that sends data to the Danish National Health Service. In addition to providing free access to medical care by general practitioners and at hospitals, the Health Service refunds part of the costs associated with outpatient prescribed drugs so prescription data for inhabitants is nearly complete.

Table 1.

Observed and expected breast cancer cases and SIRs in 32,673 users of systemic glucocorticoids, North Jutland, Denmark 1989 to 1998

The Prescription Database contains information on all prescriptions eligible for reimbursement filled in the county after January 1, 1989, including the patient’s personal identification number, the drug prescribed, and the prescription date. During the prescription exposure period from January 1, 1989, to December 31, 1996, patients prescribed the following drugs (used either p.o. or by injection) were included in the study: betamethasone, dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone. We also obtained data on all prescriptions for other cytostatic and immunosuppressive drugs (azathioprine, methotrexate, cyclosporin, mycoplexnolate, and tacrolimus) to take into account use of these agents (e.g., for cancer treatment or organ transplant).

During the prescription exposure period, 32,673 females >15 years old received a glucocorticoid prescription. Of these, 337 were excluded because they received a prescription for cytostatic or immunosuppressive drugs before their first prescription for a glucocorticoid. We linked the remaining 32,336 patients to the Danish Cancer Registry, which collects information on all individuals diagnosed with cancer, including breast cancer. Use of the personal identification number ensured a complete prescription history and unambiguous record linkage.

We followed patients for breast cancer from the first glucocorticoid prescription until death, receipt of a prescription for a cytostatic or other immunosuppressive drug, or until December 31, 1998, whichever came first. We censored 787 persons because they received a prescription for cytostatic or other immunosuppressive drugs during follow-up. Person-years were stratified by the number of reimbursed prescriptions to create categories of cumulative exposure (1, 2-4, 5-9, 10-14, and 15 or more prescriptions). The expected number of breast cancer cases was calculated as the product of the county-specific cancer incidence rates among women obtained from the Cancer Registry in strata of age (fifteen 5-year groups) and calendar year (1988-1992, 1993-1997, and 1998) and the person-years accumulated in the corresponding stratum of steroid users. The 95% confidence intervals for the standardized incidence ratios (SIR; i.e., the ratio of observed to expected cancers) were computed by Byar’s approximation. Exact limits were used when the observed number was <10. We stratified the analysis by age at the first prescription (<45, 45 + years of age) to explore whether the risk differed between premenopausal and postmenopausal women.

Results and Discussion

Of the 122,779 total corticosteroid prescriptions, 75,658 (62%) were for tablets, 47,080 (38%) were for injections, and 41 were for unknown formulations; 40% were for prednisone, 19% were for prednisolone, 14% were for triamcinolone, 17% were for betamethasone, 8% were for methylprednisone, and 2% were for other drugs. Over the study period, 367 cases of female breast cancer were observed in the cohort. The overall SIR was very near one (1.03; 95% confidence interval, 0.93-1.14). We found the lowest SIR among women with the highest number of prescriptions (SIR = 0.86; 95% confidence interval, 0.47-1.44). We did not find any substantial modification of the SIR in the analysis stratified by age at the first prescription. Our study had 80% power to detect a relative risk of 1.14 associating breast cancer with glucocorticoid prescription.

Prescription for systemic glucocorticoids was not associated with an increased incidence of breast cancer. Our study had the advantage of being a large population-based follow-up study with very little loss to follow-up. Our data lacked clinical details, in particular of the underlying diseases for glucocorticoid treatment and confounding factors aside from age. However, glucocorticoid treatment would not ordinarily be prescribed to treat breast cancer or its side effects, and confounding by indication would not ordinarily bias relative risks toward the null. Confounding factors would have to be related to glucocorticoid prescription and inversely related to breast cancer risk, conditional on adjustment for age, an unlikely combination.

Footnotes

• Grant support: Leo and Ingeborg Dannin Foundation for Scientific Research and Western Danish Research Forum for Health Sciences.

• The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

• • Accepted November 18, 2004.
  • Received August 23, 2004.
  • Revision received October 20, 2004.

References

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   Michels KB, Solomon CG, HU FB, Hankinson SE, Colditz GA, Manson JE. Type 2 diabetes and subsequent incidence of breast cancer in the nurses’ health study. Diabetes Care 2003;26:1752–8.

2. Saydah SH, Loria CM, Eberhardt MS, Brancati FL. Abnormal tolerance and the risk of cancer death in the United States. Am J Epidemiol 2003;157:1092–100.

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   Mink PJ, Shahar E, Rosamond WD, Alberg AJ, Folsom AR. Serum insulin and glucose levels and breast cancer incidence: the atherosclerosis risk in communities study. Am J Epidemiol 2002;156:349–52.

4. Dawson SI. Long-term risk of malignant neoplasm associated with gestational glucose intolerance. Cancer 2004;100:149–55.

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   Giovannucci E. Insulin, Insulin-Like Growth Factors and Colon Cancer: A Review of the Evidence. J Nutr 2001;131:3109–20S.

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   Sørensen HT, Mellemkjær L, Nielsen GL, Baron JA, Olsen JH, Karagas MR. Skin cancers and non-Hodgkin lymphoma among users of glucocorticoids: a population-based cohort study. J Natl Cancer Inst 2004;96:709.

Glucocorticoids – Knowledge @ AMBOSS

Last updated: June 3, 2021

Summary

Synthetic glucocorticoids are a group of drugs with antiinflammatory, immunosuppressant, metabolic, and endocrine effects. These drugs are structurally and functionally similar to the endogenous glucocorticoid hormone cortisol. Glucocorticoids have immediate effects (e.g., vasoconstriction) that do not depend on DNA interaction. However, they exert their main antiinflammatory and immunosuppressive actions by binding to glucocorticoid receptors, which causes complex changes in gene transcription. These genomic effects only begin to manifest after several hours. Similarly, glucocorticoids bind to mineralocorticoid receptors, but, for most glucocorticoid drugs, high doses are required for a significant mineralocorticoid effect. Systemic glucocorticoids are used for hormone replacement therapy (e.g., in Addison disease), for acute or chronic inflammatory diseases (e.g., rheumatoid arthritis), and for immunosuppression (e.g., after organ transplants). Local glucocorticoids are used to treat conditions like dermatoses, asthma, and anterior uveitis. Adverse effects include metabolic and endocrine disturbances, weight gain, skin reactions, hypertension, and psychiatric disorders; using the lowest dose possible for the shortest period of time, patient education, and regular screening can help lower the incidence of adverse effects and ensure early detection if they do occur. Contraindications for systemic glucocorticoids include systemic fungal infections and, in the case of dexamethasone, cerebral malaria. Status asthmaticus is a contraindication for inhaled glucocorticoids. Topical and ophthalmic glucocorticoids are usually contraindicated if there are preexisting local infections.

This article describes the pharmacology of synthetic glucocorticoids in detail; accordingly, glucocorticoids refer here to the drug class rather than the endogenous hormone.

Definition

Overview

• Systemic corticosteroids
  • Corticosteroids that are administered orally, intravenously, or intramuscularly
  • Act systemically as they are distributed throughout the body
  • Examples: See table below.
• Local corticosteroids (local glucocorticoids)
  • Corticosteroids that are administered topically, intraarticularly, as eye/ear drops, or are aerosolized and inhaled (inhaled corticosteroids)
  • Act primarily at the site administered; a fraction is systemically absorbed ^[4]
  • Examples: beclomethasone; , budesonide; , clobetasol; , and fluticasone
• Potency of systemic corticosteroids ^[3]

Fludrocortisone is not used for glucocorticoid activity but as a mineralocorticoid substitute in the management of adrenal insufficiency. ^[3][8]

Pharmacodynamics

1. Anti-inflammatory and immunosuppressive
   • Acute effects (within minutes)
   • Long-term effects (within hours) : Glucocorticoids bind to cytoplasmic glucocorticoid receptors (GRs)
2. Mineralocorticoid properties
   • Cortisol can bind to mineralocorticoid receptors at high concentrations ^[9]
   • Effects include, e.g., reduced sodium excretion, increased potassium excretion
3. Antiproliferative: triggers cell apoptosis, and inhibits fibroblast proliferation ^[10]
4. Anabolic-androgenic effects with steroid abuse: : increase in muscle mass and strength

Both acute and long-term effects of glucocorticoids lead to inhibition of inflammatory processes and to immunosuppression.

References:^{[11][12][13][14][15]}

Adverse effects

Glucocorticoid toxicity depends on the dose that is administered over a certain period of time. Therefore, even low doses can have toxic effects if administered long-term. If glucocorticoids are administered once or only briefly (e.g., for treatment of anaphylactic shock), there are usually no significant adverse effects even at high doses.

Many of the adverse effects listed above are also features of iatrogenic Cushing syndrome.

The tibia is BIGgA than the FIBula: cortisol increases Blood pressure, Insulin resistance, Gluconeogenesis, and Appetite; and decreases Fibroblast activity, Immune response, and Bone formation.

Local side-effects of inhaled glucocorticoids can be avoided by reducing the dose to the lowest effective amount, rinsing with mouthwash after each puff, improving the inhalation technique and compliance, and keeping vaccinations up to date.

We list the most important adverse effects. The selection is not exhaustive.

Indications

Contraindications

• General: hypersensitivity
• Systemic
• Topical
  • Dermatological: bacterial, viral or fungal infection of the mouth or throat (triamcinolone)
  • Ophthalmic
• Inhalation: status asthmaticus or acute asthma episode; requiring intensive measures (beclomethasone, budesonide)
• Relative contraindications: Glucocorticoids should be avoided in certain conditions due to increased risk of toxicity.

References:^[22]

We list the most important contraindications. The selection is not exhaustive.

Additional considerations

• Systemic administration
  • Tapering to avoid toxicity
    • Short-term administration (≤ 3 weeks): usually no tapering necessary
    • Long-term administration (> 3 weeks): tapering regimen based on patient age and condition and on duration/dose of prior glucocorticoid administration → e.g., tapering over 2 months
  • Sudden discontinuation after chronic use should be avoided because of the risk of adrenal insufficiency (adrenal crisis) secondary to long-term hypothalamic-pituitary-adrenal axis suppression.
• IM application

If the Cushing threshold is exceeded over a longer period of treatment, the glucocorticoid dose should be gradually decreased to minimize the risk of adrenocortical insufficiency.

An intratendinous injection carries the risk of bacterial spread and iatrogenic bacterial arthritis.

References:^[2][23]

Preventing complications of glucocorticoid therapy

Complications are most common with long-term systemic treatment but can also occur with higher-dose topical and inhaled steroids. The risk of complications can be reduced by keeping treatment durations short or doses low. ^[24]

Approach

^[25]

Risk assessment

Measures to prevent complications

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e.hormone | The Hormones : Corticoids

Glucocorticoids

September 04, 2015

2 min read

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Glucocorticoids are one of the corticosteroids, or steroid hormones, released from the adrenal gland. Corticosteroids are also known as adrenal cortical steroids. Glucocorticoids are synthesized and released when corticotropin, or adrenocorticotropic hormone, is released from the anterior pituitary. They bind to glucocorticoid receptors, which are present in almost every cell in vertebrate animals and are essential for the use of carbohydrate, fat and protein by the body. Glucocorticoids are necessary for the body’s normal response to stress, and they also have anti-inflammatory effects, regardless of whether they occur naturally or are synthesized.

Cortisol, or hydrocortisone, is the most important glucocorticoid in humans.

Glucocorticoid effects

There are two major categories of glucocorticoid effects: immunological and metabolic. Conditions that cause inflammation or overactive immune response such as allergies, asthma, autoimmune diseases and sepsis are often treated by glucocorticoids. Glucocorticoids also have demonstrated an ability to interfere with some of the abnormal mechanisms in cancer cells.

Regarding the metabolic effects of glucocorticoids, cortisol stimulates several processes that increase and maintain glucose concentrations in the blood. Other metabolic effects include the stimulation of glucogenesis in the liver; the mobilization of amino acids in extrahepatic tissues; inhibition of glucose uptake in muscle and adipose tissue; and stimulation of fat breakdown.

Low doses of glucocorticoids may be used to treat renal insufficiency.

The development and homeostasis of T lymphocytes may be affected by glucocorticoids, and glucocorticoids may also effect fetal development by promoting lung function.

When glucocorticoids are administered as a drug, or when hyperadrenocorticism occurs, excessive levels of the hormones may affect bone formation, suppression of calcium absorption, delayed wound healing, muscle weakness and increased risk for infections.

Mechanisms of action

The two mechanisms of action of glucocorticoids include transactivation and transrepression. They act on the hippocampus, amygdala and frontal lobes. These help regulate metabolic and cardiovascular functions.

Treatment with glucocorticoids

Glucocorticoids inhibit swelling and are used to treat inflammation in diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis and eczema. Both natural and synthetic glucocorticoids are used in treatment.

However, long-term use of oral glucocorticoids has been associated with osteoporosis, metabolic disease and a heightened risk for cardiovascular disease.

Glucocorticoids also slow immune responses and have been used in the treatment of autoimmune diseases and in preventing graft rejection. Those taking medications that weaken the immune system, like corticosteroids, can be at greater risk for fungal infection.

Neutrophilia may occur with acute or chronic use of corticosteroids. Other adverse effects include hyperglycemia, increased skin fragility, negative calcium balance, steroid-induced osteoporosis, weight gain, adrenal insufficiency, muscle breakdown, growth failure, increased amino acids, glaucoma or cataracts.

Additional information may be found at these websites:

http://bloodjournal.hematologylibrary.org/cgi/collection/gene_expression

http://www.nlm.nih.gov/medlineplus/ency/article/003706.htm

http://www.mayoclinic.com/health/metabolism/WT00006/

http://www.nature.com/jcbfm/index.html

http://www.nutritionandmetabolism.com/

http://www.hormone.org/Public/endocrinologist. cfm

http://www.nlm.nih.gov/medlineplus/ency/article/002257.htm

http://www.ncbi.nlm.nih.gov/books/NBK22/?depth=10

http://endo.endojournals.org/

http://www.mayoclinic.org/medicalprofs/glucocorticoid-induced-diabetes.html

http://www.nlm.nih.gov/medlineplus/steroids.html

http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors

http://www.ncbi.nlm.nih.gov/gene/2099

http://ghr.nlm.nih.gov/glossary=enzyme

http://www.nlm.nih.gov/medlineplus/ency/article/002353.htm

http://www.drugs.com/drug-class/glucocorticoids.html

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047790/

http://www.ncbi.nlm.nih.gov/pubmed/15265777

http://www.cdc.gov/fungal/infections/immune-system.html

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Analysis # AN65COR, Cortisol for dogs and cats: indicators, norm

Cortisol is the main steroid hormone secreted by the adrenal cortex. Most of the cortisol in the blood is bound to plasma proteins, and only 10% of the total circulating cortisol is in a free, metabolically active form. This hormone affects the metabolism of carbohydrates, proteins and lipids, stimulates gluconeogenesis and induces peripheral insulin resistance by suppressing the transport of glucose into cells.

1. Preanalytics
2. Interpretation of the result
3. Reference values ​​

Cortisol also has an anti-inflammatory effect, in part as a result of its effect on white blood cells. Neutropenia, mild lymphocytosis, and eosinophilia are characteristic changes in cortisol deficiency. Also, a decrease in cortisol levels can be accompanied by non-regenerative anemia and a decrease in hematocrit, which result from the absence of the stimulating effect of steroid hormones on the bone marrow.In contrast, an excess of endogenous or exogenous glucocorticoids can induce leukocytosis in dogs and cats.

Leukogram (“stress leukogram”) is characterized by neutrophilia with a predominance of mature (segmented) forms, lymphopenia and eosinopenia. Monocytosis can be detected in dogs, which is usually not found in cats.

Neutrophilia with a shift to the right is caused by several factors, such as increased release of neutrophils from the bone marrow, the movement of neutrophils from the marginal pool into the circulatory bed, and a slowdown in the passage of neutrophils from the blood to tissues.

Lymphopenia is the result of redistribution of circulating lymphocytes. In addition, high doses of glucocorticoids can lead to lymphocyte lysis. Eosinopenia is caused by inhibition of the release of eosinophils from the bone marrow and sequestration of eosinophils in tissues. In dogs, excess glucocorticoids can cause thrombocytosis.

Glucocorticoids are involved in the normal functioning and maintenance of the integrity of the gastrointestinal tract.An excess of glucocorticoids causes a slowdown in the growth and renewal of cells in the gastric mucosa and a decrease in mucus secretion, which leads to a disruption of the barrier function of the gastric mucosa. Glucocorticoid therapy can lead to gastrointestinal bleeding, ulceration, and colon perforation.

The effect of glucocorticoids on the central nervous system (CNS) is to maintain adequate concentrations of glucose in the blood, which is necessary for the normal functioning of the brain, maintenance of cerebral blood flow and electrolyte balance in the central nervous system.Glucocorticoids reduce the formation of cerebrospinal fluid, are involved in the regulation of neuronal excitation and, possibly, have a neuroprotective effect.

Cortisol and some synthetic glucocorticoids have mineralocorticoid activity. Depending on the concentration or dose, they cause sodium retention and potassium loss through the kidneys.

Glucocorticoids have a positive inotropic and chronotropic effect on the heart. Since glucocorticoids increase the sensitivity of receptors to catecholamines, they thereby contribute to the maintenance of normal vascular tone.Glucocorticoids reduce capillary permeability by inhibiting the activity of kinins and bacterial endotoxins, as well as by reducing the amount of histamine released by basophils. Prolonged exposure to stress can cause refractory shock in glucocorticoid-deficient individuals.

An excess of glucocorticoids can lead to the development of hypertension by activating various mechanisms, such as an increase in mineralocorticoid activity, activation of the renin-angiotensin-aldosterone system (RAAS), prostacyclin and kallikrein-kinin system, etc.The exact mechanisms of these processes in dogs and cats have not yet been established. Glucocorticoids increase the number and affinity of beta-2 receptors, thereby promoting bronchodilation.

Regulation of cortisol synthesis is carried out through the hypothalamic-pituitary system according to the principle of negative feedback. Cortisol is released in response to the action of adrenocorticotropic hormone (ACTH) produced in the anterior pituitary gland. The production of ACTH is under the control of the peptide corticotropin-releasing hormone of the hypothalamus.An increase in the level of cortisol in the blood inhibits the secretion of corticotropin-releasing hormone in the hypothalamus, as a result of which the production and release of ACTH from the pituitary gland and the secretion of cortisol by the adrenal glands decrease.

An increase in the level of cortisol in the blood (both endogenous and exogenous) contributes to the excessive deposition of glycogen in the liver (in dogs) and an increase in the activity of liver enzymes. When stress-induced high blood cortisol levels persist for a long time, alkaline phosphatase activity can increase in animals.As a result of the pulsating nature of cortisol release, animals with hyperadrenocorticism and hypoadrenocorticism often have cortisol levels that are within the reference range. In addition, basal cortisol levels can rise as a result of stress caused by transportation, hospitalization, medical treatment, or the development of severe acute or chronic illness.

The main disease of the glomerular adrenal cortex is hyperadrenocorticism, or Itsenko-Cushing’s disease .This disorder is usually secondary to the development of a pituitary adenoma, in which there is an excessive secretion of ACTH.

Hyperadrenocorticism can also be caused by adrenal cortex tumor , which produces glucocorticoids autonomously, or by iatrogenic route as a result of glucocorticoid administration. Regardless of the cause, all clinical signs and changes in laboratory parameters in hyperadrenocorticism are due to an increase in serum cortisol.

In dogs, cats and horses, the reticular adrenal cortex, which synthesizes glucocorticoids and sex hormones, plays a minor role in the development of hyperadrenocorticism. In ferrets, this area is of great importance, since most of the clinical disorders are due to an increase in the level of sex steroids.

Primary hypoadrenocorticism is associated with bilateral adrenal injury and accounts for the majority (over 95%) of canine hypoadrenocorticism.The loss of more than 90% of adrenal cortex function is required before clinical signs of glucocorticoid and mineralocorticoid insufficiency develop, therefore the clinical manifestation of hypoadrenocorticism occurs only in the case of bilateral dysfunction of the adrenal cortex.

Secondary hypoadrenocorticism results from decreased secretion of ACTH from the pituitary gland and is a less common cause of adrenal insufficiency. A decrease in the level of ACTH causes atrophy of the adrenal cortex (not affecting the reticular area of ​​the adrenal glands) and impaired secretion of glucocorticoids, which does not affect the synthesis of mineralocorticoids.

Determination of the basal blood cortisol concentration provides limited information on the function of the adrenal cortex. However, the measurement of cortisol levels is useful in a number of stimulatory or suppressive tests that provide more complete information about the function of the adrenal cortex in cases of suspected development of hyperadrenocorticism or hypoadrenocorticism.

Preanalytics:

Before the study, animals should be on a fast diet for at least 12 hours.Stability of cortisol in blood serum is five days at a storage temperature of + 2 ° C … + 8 ° C, two months at a storage temperature of -17 ° C … -23 ° C (subject to the preanalytical requirements for taking biomaterial for hormonal research).

Interpretation:

The results of the study contain information exclusively for doctors. The diagnosis is made on the basis of a comprehensive assessment of various indicators and additional information.

Units of measurement: nmol / l.

Conversion of units of change: μg / dl x 27.6 (nmol / l).

Reference values:

Dogs: 28-170.0 nmol / L.
Cats: 28-140.0 nmol / L.

If hyperadrenocorticism is suspected and a definitive diagnosis is made, functional tests (ACTH-stimulating or suppressive tests with dexamethasone) are required.

In dogs with hyperadrenocorticism, basal cortisol levels are often within the reference range.Cortisol levels are influenced by stress and comorbidities not directly related to diseases of the hypothalamic-pituitary-adrenal system.

In dogs suspected of developing hypoadrenocorticism, a cortisol value of less than 28 nmol / L will confirm the diagnosis if clinical signs of disease are present. At the same time, a cortisol value of more than 140 nmol / l excludes the diagnosis. With intermediate values ​​of cortisol (from 28 nmol / l to 140 nmol / l), the diagnosis of hypoadrenocorticism is not definitive.

Level Up:

• Hyperadrenocorticism
• Stress
• Severe diseases not directly related to the pathology of the adrenal cortex
• Taking medications (prednisone or other steroid hormones)
• Increase in estrogen in the blood (estrus)
• Violation of preanalytics

Derating:

• Hypoadrenocorticism (including iatrogenic)
• Action of gestagens
• Violation of preanalytics

Actual problems of short stature in children and adolescents: classification, features of clinical therapy of variants of the disease | Kasatkina

Abstract

The article is devoted to topical problems of short stature in children and adolescents, classification, features of clinical therapy of variants of the disease.

Growth retardation is a common reason for children seeking an endocrinologist: about 3% of the child population has a pronounced growth retardation. At the same time, growth hormone (GH) deficiency as a cause of short stature is detected in no more than 8.5%. In the rest of the children, constitutional features of growth and development are most often revealed, less often – a deficiency of other anabolic hormones, severe somatic diseases, genetic and chromosomal diseases. In recent years, the problem of identifying patients with GH deficiency as a cause of growth retardation has become especially urgent.This is due to the fact that recombinant human GH is used as hormone replacement therapy in this group of patients. The drug has a good growth effect. This effect is especially pronounced in patients with growth retardation due to GH deficiency. In this regard, the identification of such patients among children with nanism is a very important stage in the chain of measures aimed at normalizing the growth of children. This circumstance dictates the need to remind pediatricians of a wide profile about the heterogeneity of nanism in children, to present all the variety of forms of the disease occurring with growth retardation, to give the key symptoms of each variant of the disease that facilitate the diagnosis, differential diagnosis of nanism and the selection of patients for the treatment of GH.I. Endocrine-dependent variants of growth retardation The most severe disorders of growth processes are observed in pathology of the endocrine system. It is known that hormones are directly or permissively involved in growth processes. The most pronounced growth effect is provided by growth hormone (GH). It accelerates the synthesis of amino acids and their inclusion in the protein molecule, which is carried out with the help of somatomedins – insulin-like growth factors (IGF). In addition to the pronounced growth effect, GH has a lipolytic and glycogenolytic effect, and also stimulates the secretion of insulin by the pancreas, i.e.e. improves energy metabolism. Thyroid hormones (TG) in physiological quantities have a significant anabolic effect. Unlike GH, these hormones affect to a greater extent the differentiation (maturation) of tissues, primarily bone. At the same time, TG, actively influencing the level of GH, accelerate the linear growth of the child. Insulin plays an important role in the regulation of growth processes, since, on the one hand, it provides anabolic processes energetically, on the other hand, it directly enhances protein synthesis.Sex hormones have a powerful anabolic effect, accelerating both linear growth and differentiation of the bones of the skeleton. However, it should be remembered that the growth effect of sex hormones occurs only in the presence of GH. Glucocorticoids, enhancing the processes of gluconeogenesis, have a pronounced catabolic effect. High doses of cortisol have a negative effect on the growth processes due to the fact that it actively inhibits the release of GH. The combined action of the above hormones ensures normal growth and development processes.The final growth of an adult is also largely determined by the timing of the onset and duration of puberty, that is, the timing of the final fusion of the epiphyseal clefts. So, growth retardation and lagging in bone age are a symptom of many endocrine diseases, which are characterized by a deficiency of anabolic or excess catabolic hormones. Cerebral-pituitary dwarfism (CPH) is characterized by the loss of all tropic hormones (panhypopituitarism). Distinguish between idiopathic and organic variants of the disease.With the idiopathic variant of the CGN, there are no signs of organic lesion of the central nervous system, the pathological process is formed at the level of hypothalamic structures. In boys, the disease occurs 2-4 times more often than in girls. The clinical picture of the disease is due to a deficiency of tropic hormones and therefore a violation of the function of the endocrine glands. At the same time, the symptoms of GH deficiency dominate, i.e., there is a pronounced proportional growth retardation. In the absence of treatment, the height of adult patients does not exceed 120 cm in women and 130 cm in men.At birth and in the first months of life, the physical development of children with CPG does not differ from that of healthy children. Growth retardation becomes noticeable in the 2nd year of life. Gradually, the growth rate decreases, and after 4 years of life, children add no more than 2-3 cm per year. Bone age lags significantly behind chronological age. In addition to growth retardation in children with GH deficiency, there is a tendency to hypoglycemic conditions (glycogenolysis processes are reduced). Hypoglycemia in some children can be the first sign of the disease and is often detected already during the neonatal period.Deficiency of thyroid-stimulating hormone in patients with CPG is the cause of hypothyroidism, which determines a complex of characteristic symptoms: mental lethargy, dry skin, bradycardia, hypotension, constipation, late appearance and late change of teeth. A pronounced TG deficiency further impairs the growth and differentiation of skeletal bones in patients with CPG. Deficiency of gonadotropic hormones (GTH) is the cause of hypogonadism. Some boys with CGN already at birth have signs of intrauterine thyroid hormone deficiency: cryptorchidism and microfallos.In the future, all patients show symptoms of severe hypogonadism: secondary sexual characteristics are absent, growth zones remain open. The pronounced deficiency of sex hormones and the absence, as a result of this, of a pubertal growth spurt in such children further aggravates the growth retardation. Most patients with CPG have ACTH deficiency and hypocorticism, however, outside stressful situations, the symptoms of hypocorticism in patients, as a rule, are not detected. Against the background of therapy with thyroid and anabolic drugs, the need for glucocorticoids increases and symptoms of adrenal insufficiency can be detected, more often in response to a stressful situation.In the organic variant of CPG, damage to the hypothalamic-pituitary system may occur due to congenital defects (aplasia or hypoplasia, aneurysm) or destructive damage. However, the most common in such patients is a congenital tumor – craniopharyngioma. In addition to growth retardation in patients with an organic variant of CGN, attention is drawn to pronounced neurological symptoms, signs of increased intracranial pressure, and limitation of visual fields. As the process progresses and other tropic hormones fall out, symptoms of hypothyroidism, hypocorticism, hypogonadism appear.Diabetes insipidus, sometimes transient, is characteristic of this variant of the disease. With an isolated GH deficiency, other tropic hormones are secreted in normal amounts, and therefore a more favorable course of the disease is observed: the growth of adult patients is slightly higher (in women – 125 cm, in men – 145 cm), there are no symptoms of hypothyroidism, puberty usually occurs by 2 -4 years later, but proceeds normally, patients are usually fertile. Bone age lags behind chronological age, but the differentiation of skeletal bones is disturbed to a lesser extent than in CPG.At the end of puberty, the growth zones in patients are closed. Currently, three more variants of isolated GH deficiency are known: partial GH deficiency, selective GH deficiency, and psychological dwarfism. Partial GH deficiency occurs in about 10% of patients with isolated GH deficiency. This variant of the disease is characterized by incomplete loss of GH and a milder clinical course of the disease. Neurosecretory dysfunction is characterized by a dysregulation of GH synthesis and a decrease, due to this, in the spontaneous secretion of GH.In this case, only one of the regulatory mechanisms (catecholamine, serotonin or dopamine) can be disrupted. Psychological dwarfism can occur in children from disadvantaged families. Such children develop pronounced growth retardation, bone age, mental development, the presence of GH deficiency has been proven. When these children are isolated from unfavorable conditions, the level of GH is restored on its own, children begin to grow, however, the lag in intellectual development remains for life.A rare variant of growth retardation – Laron’s syndrome – is caused by a defect in GH receptors. The clinical picture in patients with a similar syndrome is identical to the clinical picture of isolated GH deficiency. However, the level of GH in patients usually exceeds normal levels. The absence of the effect of GH is explained by a decrease in the level of somatomedins (primarily IGF1), the synthesis of which does not increase with the introduction of exogenous GH. Family cases of the disease have been described, and consanguineous marriages are often registered in these families. We cannot exclude the possibility of the development of growth retardation variants, which are also caused by a violation of the biological activity of GR.The key clinical symptom of GH deficiency is a pronounced proportional growth retardation: the growth rate of children does not exceed 4 cm per year, the growth retardation exceeds 2 sigma deviations, the bone age lags significantly behind the chronological age, and the ratio of bone age to chronological age is less than 0.9. The level of GH in the blood (basal and stimulated) in patients of this group does not exceed 15 mU / L, more often it is much lower. In addition to GH deficiency (or a violation of the mechanism of its action), pronounced growth retardation in children may be due to a deficiency of other anabolic hormones (thyroid, sex, insulin).Thus, hypothyroidism, hypogonadism (in adolescence) and Moriak’s syndrome (in patients with severe diabetes mellitus) are characterized by growth retardation and bone age. Pronounced short stature as a result of premature closure of growth zones always occurs in patients with premature puberty of any etiology. High levels of glucocorticoids (Itsenko-Cushing’s disease}, which have a catabolic effect, can also cause growth retardation in children.Diagnosis of such variants of growth retardation is not difficult, since the characteristic symptoms of the underlying endocrine disease come to the fore in the clinical picture.Difficulty in the differential diagnosis of these conditions can arise only when a patient with a mild variant of primary congenital hypothyroidism has a proportional delay in growth and bone age (monosymptomatic variant of the disease) and there are no other typical symptoms of congenital hypothyroidism. The peculiarities of the hormonal profile of these diseases make it easy to establish the correct diagnosis. An increase in the TSH level and a normal level of GH against the background of stimulation (after saturation with TG) make it possible to exclude a patient with a growth hormone deficiency as a cause of growth retardation and to establish a diagnosis of primary hypothyroidism (monosymptomatic variant).II. Endocrine-independent options for growth retardation Significantly more often in patients with growth retardation, there are no signs of dysfunction of the endocrine glands, that is, in most children, growth retardation is due to non-endocrine factors. Severe somatic diseases, which result in conditions of prolonged hypoxia (congenital heart defects, anemia, lung diseases), malabsorption (celiac disease, cystic fibrosis). Severe metabolic disorders (chronic liver and kidney diseases), as well as pathology of the skeletal system (chondrodystrophy, gargoilism and other congenital syndromes) are often accompanied by severe growth retardation.With these variants of nanism, there are no signs of primary dysfunction of the endocrine glands, bone age, as a rule, corresponds to the chronological one. The symptoms of the underlying disease come to the fore, which makes it easy to establish the cause of growth retardation. Primordial nanism (intrauterine, primary). A feature of this variant of growth retardation is a violation of growth processes from the period of intrauterine life. Full-term newborns with this pathology have insufficient length and body weight.At all stages of life, children with primordial nanism lag significantly behind their peers in growth. However, unlike children with endocrine-induced growth retardation, the bone age in these children corresponds to the chronological age, the pubertal period, as a rule, occurs at the usual time. The GH level is in line with normal values. There is no doubt that the group of children with primordial nanism is heterogeneous. In this group, patients are united according to one main feature – a violation of growth processes from the period of intrauterine life: genetic syndromes (Seckel, Russell-Silver, etc.), intrauterine infection (rubella, syphilis, toxoplasmosis, cytomegaly), “alcoholic fetus”, etc. A characteristic feature of Shereshevsky-Turner syndrome is a pronounced growth retardation. In the classic version of the syndrome (karyotype 45X0), the growth of patients does not exceed 142-145 cm, with mosaicism (45X0 / 46XX), the growth may be slightly higher. At birth, children with this Syndrome have normal indicators of length and body weight, growth retardation begins to attract attention from the age of 2-3 years. From this time on, the growth rate decreases to 2-3 cm per year.Bone age, as a rule, up to 11 -12 years old corresponds to the chronological age, later due to pronounced hypogonadism it lags behind the chronological one. In the classical variant of the disease, secondary sexual characteristics are absent, in mosaicism, they can be expressed to varying degrees. A large number of characteristic dysplastic symptoms and a negative or low percentage of sex chromatin confirm the diagnosis. Shereshevsky-Turner syndrome is the most common (~ 20-30%) cause of stunted growth in girls.In boys with stunted growth, constitutional stunted growth and puberty (late puberty syndrome) or familial short stature are most common. Constitutive growth retardation and puberty – late puberty syndrome – is characterized by features of growth and development of a hereditary nature. Usually, the parents and / or closest relatives of these children have the same developmental characteristics. So, the length and weight of the body at birth do not differ from those of healthy children.The lowest growth rates take place in the first years of life and, therefore, the most pronounced growth retardation is observed in children aged 3-4 years. From 4-5 years of age, growth rates are restored (5-6 cm per year), however, having initially low growth, children remain stunted at school age. Bone age is slightly (on average 2 years) behind chronological age. This circumstance can explain the late entry into puberty: usually, sexual development and, consequently, the pubertal growth spurt are delayed in these children by 2-4 years.In this regard, adolescents with late puberty syndrome lag sharply behind their peers in their development. Late entry into puberty in this case should be recognized as a favorable factor, since it allows patients with similar features of constitutional development to ultimately have normal growth. When conducting differential diagnostics of options for growth retardation in boys, it should be remembered that about 80% of adolescents with growth retardation and sexual development have this constitutional feature of growth and development.Family short stature. Among the relatives of children with a similar variant of growth retardation, there are always stunted ones. At birth, children have normal growth rates and body weight, but the growth rate after 3-4 years is 2-4 cm per year. It is fundamental that the bone age of these children usually corresponds to the chronological age and, therefore, the entry of children into puberty corresponds to normal periods. This circumstance is the reason for the short stature of adult patients with these developmental features.It cannot be ruled out that the cause of family short stature is the constitutional characteristics of the synthesis and secretion of GH. Based on the data presented, the classification of nanism in children can be presented as follows. CLASSIFICATION OF GROWTH DELAY IN CHILDREN 1. Endocrine-dependent variations 1.1. GH deficit 1.1.1. tsg 1.1.1.1. Idiopathic variant (panhypopituitarism) 1.1.1.2. Organic option 1.1.2. Isolated GH deficit 1.1.2.1. Significant deficit of GRs 1.1.2.2. Partial GH deficit 1.1.2.3. Neurosecretory dysfunction 1.1.2.4. Psychological dwarfism 1.1.3. Laron’s syndrome 1.2. TG deficiency 1.2.1. Hypothyroidism 1.2.2. Monosymptomatic variant of congenital primary hypothyroidism 1.3. Insulin deficiency 1.3.1. Moriak’s syndrome, Nobekura 1.4. Sex hormone deficiency 1.4.1. Primary hypogonadism 1.4.2. Secondary hypogonadism 1.5. Excess sex hormones 1.5.1. Premature puberty (after the end of puberty) 1.6. Excess glucocorticoids 1.6.1. Itsenko-Cushing’s disease 2.Endocrine-independent variants 2.1. Somatogenically caused Congenital and acquired diseases, accompanied by: 2.1.1. chronic hypoxia 2.1.2. chronic anemia 2.1.3. violation of absorption processes 2.1.4. impaired renal function 2.1.5. impaired liver function 2.2. Bone system pathology 2.3. Genetic and chromosomal syndromes 2.3.1. Primordial nanism 2.3.2. Shereshevsky-Turner syndrome 3. Constitutional features of physical development 3.1. Late puberty syndrome 3.2. Family short stature So, growth retardation in children is a heterogeneous state. The most pronounced forms of the disease are caused by GH deficiency. In the past, patients with GH deficiency were the most unpromising in terms of treatment. The situation has now changed. It is this group of children on the background of hormone replacement therapy with recombinant human GH that gives the most pronounced increase in growth. Moreover, there have been cases of normalization of growth in patients with prolonged hormone replacement therapy.In this regard, the differential diagnosis of nanism, the identification of children with GH deficiency, that is, the selection of patients for drug treatment, is a very urgent task of modern clinical endocrinology.

1. Vasyukova E. A., Kasatkina E. P. Growth disorders.- M., 1981.- S. 1-15.

2.Evaluation of growth hormone secretion: Physiology and clinical application. // Pediatric and Adolescent. Endocrinology Karger, 1983. – Vol. 12.- P. 1-199.

3. Growth II Pediatric Endocrinology / Ed. F. Lifshitz. – New York, 1985. – P. 1-139.

90 130 90 000 Hyperadrenocorticism Cushing’s syndrome in dogs

Hyperadrenocorticism, HAC or Cushing’s syndrome is one of the most common endocrinopathies in dogs and rarely seen in cats.
GAC is a condition associated with a chronic excess of glucocorticoids in the blood.

The most active and main endogenous glucocorticoid is cortisol, it is its concentration in the blood that increases with spontaneous HAC.
Cortisol is a steroid hormone secreted by the adrenal cortex that gives the body a sense of anxiety.

Main symptoms hyperadrenocorticism

Associated with excess cortisol in the body:

• polydipsia / polyuria (thirst and increased urination)
• change in pet’s constitution – increased saggy belly, reduced muscle mass
• skin lesions – alopecia (hairless areas), skin calcification, comedones
• prolonged anestrus in bitches (no leaks) and testicular atrophy in males

Causes of Cushing’s syndrome in dogs:

• long-term use of glucocorticoids (prednisolone, metipred, desfort)
• ACTH hypersecretion by pituitary adenoma
• hypersecretion of cortisol by adrenal tumor

Diagnosis of Cushing’s syndrome

• Urinary cortisol / creatinine (to exclude HAC, but not to confirm)
• Small desamethasone test
• Stimulating test with ACTH

Treatment of Cushing’s syndrome in dogs

SAC treatment is aimed at improving the quality of life and preventing complications.
Irrepressible appetite, thirst and increased urination should disappear, the quality of skin and coat, physique and cycle in bitches should be normalized.
To do this, it is necessary to normalize the concentration of cortisol in the blood and prevent the reverse process – iatrogenic Addison’s disease.
For this purpose, to control therapy, stimulation tests with ACTH

are carried out every 3 months throughout life.

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Too salty food depresses your immune system

A diet high in salt weakens the body’s natural defenses against bacterial infections.

German scientists have noticed that a diet rich in sodium chloride can significantly weaken the body’s natural defenses against bacterial infections.

The fact is that the kidneys play an important role in filtering out excess salt. But as a side effect, it also leads to a buildup of a substance in the body that interferes with the activity of an important type of immune cell in the blood that is responsible for fighting bacteria.

Scientists have conducted a study on laboratory mice fed a high-salt diet and found that urinary tract infections were much slower to heal.

In another experiment, they examined the ability of mice to fight off listeria infections that can occur through contaminated food and lead to fever.

As it turned out, in mice with listeria infection, which ate a diet high in salt, scientists counted 100-1000 times more pathogens in the spleen and liver than in their relatives who do not abuse salty food.

Another experiment involved people who ate an additional six grams of salt in excess of their daily intake.Using their example, the researchers found that additional salt increases glucocorticoid levels, which significantly impairs the body’s ability to fight bacteria.

“Now, for the first time, we have been able to prove that excessive salt intake also significantly weakens an important part of the immune system,” explains Prof. Dr. Christian Kurz from the Institute for Experimental Immunology at the University of Bonn.

Earlier “Kubanskie Novosti” told how salt spoils your figure.

Congenital dysfunction of the adrenal cortex (Resident of KazNMU named after S.D. Asfendiyarov Hasanov A.)

Congenital dysfunction of the adrenal cortex

Resident of KazNMU them. S. D. Asfendiyarova Hasanov A.

Congenital dysfunction of the adrenal cortex (synonym: adrenogenital syndrome, congenital virilizing hyperplasia of the adrenal cortex, Aper – Halle syndrome) – a disease based on a violation of the synthesis of steroid adrenal hormones.The most common cause of this disorder is a congenital defect in the enzyme systems of 21-hydroxylase (steroid-21-hydroxylase) and 11b-hydroxylase (steroid-11b-hydroxylase), which are involved in the synthesis of glucocorticoids and mineralocorticoids: impaired glucocorticoid synthesis leads to cortisol deficiency. The 21-hydroxylase defect causes the development of two clinical forms of the disease – uncomplicated (simple, or virilizing) and salt-losing, and the 11b-hydroxylase defect causes the development of the hypertensive form. Compensation of hormonal imbalance caused by a violation of the synthesis of corticosteroids is ensured by the fact that the hypothalamic-pituitary system produces increased amounts of ACTH, and the adrenal glands in excess secrete glucocorticoid precursors (mainly 17-OH-progesterone) and androgens, i.e.That is, those steroids, in the synthesis of which defective enzyme systems do not take part.

The scheme of violation of steroidogenesis is the same for all forms of V. However, with the salt-wasting form, the synthesis of mineralocorticoids is also impaired. The resulting deficiency of aldosterone is the reason for the increased excretion of sodium in the urine, dehydration, potassium retention, azotemia, the development of acidosis, and an increase in blood plasma renin activity. In the hypertensive form, in addition to a deficiency of cortisol and an excess of androgens, a pronounced violation of the synthesis of mineralocorticoids is noted, accompanied not only by a deficiency of aldosterone, but also by overproduction of the precursor of aldosterone, deoxycorticosterone, which has sodium-retention and hypertensive effects.

Clinical picture with uncomplicated form V. characterized by virilization of the body. In the fetus, the adrenal glands begin to function from the 12th week of intrauterine life, when gender differentiation occurs, therefore, an excess of adrenal androgens causes intrauterine virilization of the female fetus, leading to the development of false female hermaphroditism. In a male fetus, an excess of androgens does not interfere with the normal course of the sex differentiation process. After birth, excess androgens cause androgenization in girls and hyperandrogenism in boys.

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Canine hyperadrenocorticism (HAC)

Canine hyperadrenocorticism (HAC)

31.01.2019
Hyperadrenocorticism is a disease characterized by excessive secretion of adrenal cortex hormones, cortisol.
Distinguish between primary (85-90% of cases) and secondary (10-15% of cases) hyperadrenocorticism.

Primary HAC is caused by neoplasia or hyperplasia of the pituitary gland and is accompanied by increased secretion of adrenocorticotropic hormone. Secondary HAC develops with a cortisol-secreting neoplasm of the adrenal gland (adenoma or carcinoma).
The cause of iatrogenic HAC is the excessive introduction of glucocorticoids into the body
HAA is one of the most common diseases in dogs; it is quite rare in cats. Most often, middle-aged and elderly animals get sick.
The severity of clinical manifestations depends on the degree of excess cortisol and the duration of exposure to the body.

Disease symptoms

• Polydipsia, polyuria, polyphagia
• Lethargy
• Dermatological changes: symmetrical alopecia, poor hair regrowth, acne, “thinning of the skin (” parchment “skin)
• Bloating (“pear-shaped” abdomen, sagging abdominal wall)
• Rapid breathing
• Muscle weakness
• Anestrus and genital hypotrophy
• Rare signs of hyperadrenocorticism
• Dermatological changes: discoloration of the coat, hyperpigmentation, calcification of the skin Chronic infections / non-healing wounds (e.g. cystitis, pressure ulcers)
• Pseudomyotonia (leading to tense gait of the hind legs)
• Pulmonary thromboembolism (causing shortness of breath)
• Neurological signs (due to rapid tumor growth): ataxia, depression, blindness

Diagnostics

Routine blood tests (biochemical and general clinical), general urinalysis, measurement of corticoids in urine.
As well as specific endocrine tests: ACTH stimulation test, suppressive test with a low dose of dexamethasone.
Ultrasound of the adrenal glands, MRI of the brain.
After the diagnosis is made, the animal is prescribed drugs that will significantly improve the general condition, but will not eliminate the cause of the problem.

Treatment options

Medical or surgical treatment
A number of drugs have been proposed for the treatment of GAC. These include, but are not limited to, trilostane, mitotane, ketoconazole, and selegeline.
If doctors are faced with cases in which the cause of hyperadrenocorticism is unknown, then it is permissible to use trilostane or mitotane, since both are effective drugs against both forms of GAC. However, the response to treatment and the likely prognosis may vary.

References and Further Reading Anderson CR. Birchard SJ. Powers BE. Belandria GA. Kuntz CA. Withrow SJ. (2001) Surgical treatment of adrenocortical tumors: 21 cases (1990-1996) Journal of the American Animal Hospital Association 37: 93-7 Barker E., Campbell S., Tebb A., Neiger R., Herrtage M., & Ramsey I. (2005) A comparison of the survival times of dogs treated for hyperadrenocorticism with trilostane or mitotane Journal of Veterinary Internal Medicine 19: 810-815 Bell R., Neiger R., McGrotty Y. & Ramsey IK. (2006) Effects of once daily trilostane administration on cortisol concentrations and ACTH responsiveness in hyperadrenocorticoid dogs Veterinary Record 159: 277-281 Chapman, P.S., Mooney, C.T., Ede, J., Evans, H., O’Connor, J., Pfeiffer, D.U. & Neiger, R. (2003) Evaluation of the basal and postadrenocorticotrophic hormone serum concentrations of 17-hydroxyprogesterone for the diagnosis of hyperadrenocorticism in dogs. Veterinary Record 153, 771-775. Chapman PS. Kelly DF. Archer J. Brockman DJ. And Neiger R. (2004) Adrenal necrosis in a dog receiving trilostane for the treatment of hyperadrenocorticism. Journal of Small Animal Practice. 45: 307-10 Eastwood JM., Elwood CM. and Hurley KJ. (2003) Trilostane treatment of a dog with functional adrenocortical neoplasia.Journal of Small Animal Practice. 44: 126-31 Gould, S.M., Baines, E.A., Mannion, P.A., Evans, H. & Herrtage, M.E. (2001)

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90,000 – corticoid function – Biochemistry

The hormones of the pituitary-adrenal system include adrenocorticotropic hormone (ACTH), which regulates the activity of the adrenal cortex, and glucocorticoids (corticosteroids) synthesized in this cortex.Determining the amount of hormones in this system is used to diagnose the causes and understand the pathogenesis of various diseases.

Proopiomelanocortin is a 254 amino acid peptide. During its hydrolysis, a number of hormones are formed in the cells of the anterior and intermediate pituitary gland: α-, β-, γ-melanocyte-stimulating hormones, adrenocorticotropic hormone, β-, γ-lipotropins, endorphins, met-enkephalin.

Adrenocorticotropic hormone

Building

It is a peptide containing 39 amino acids.

Regulation of synthesis and secretion

Activate: corticoliberin, synthesized during stress (anxiety, fear, pain) under the influence of nerve signals from brain structures, vasopressin, angiotensin II, catecholamines.
ACTH also has its own daily rhythm – the maximum concentration in the blood is reached in the morning hours, the minimum at midnight.

Decrease: glucocorticoids (negative feedback).

Mechanism of action

Activating adenylate cyclase.

Targets and Effects

In adipose tissue stimulates lipolysis.

In adrenal glands (mainly in the reticular and bundle zones) stimulates the formation of protein and nucleic acids for the growth of their tissue, activates the synthesis of cholesterol de novo and its production from esters, enhances the synthesis of pregnenolone …

Pathology

Hypofunction

Possible with pituitary insufficiency, accompanied by a decrease in the activity of the adrenal cortex.

Hyperfunction

Manifested by Itsenko-Cushing’s disease – symptoms of hypercortisolism (see below) and specific symptoms:

• lipolysis activation,
• increase skin pigmentation due to a partial melanocyte-stimulating effect, hence the term “bronze disease”.

Glucocorticoids

Building

Glucocorticoids are cholesterol derivatives and are steroidal in nature.The main hormone in humans is cortisol.

The structure of glucocorticoids

Synthesis

It is carried out in the reticular and fascicular zones of the adrenal cortex. Formed from cholesterol, progesterone is oxidized by 17-hydroxylase at the 17th carbon atom. After that, two more important enzymes come into action in sequence: 21-hydroxylase and 11-hydroxylase. Ultimately, cortisol is produced.

Scheme of the synthesis of steroid hormones (complete scheme)

Regulation of synthesis and secretion

Activate: ACTH, which provides an increase in the concentration of cortisol in the morning, by the end of the day, the content of cortisol decreases again.In addition, there is a nervous stimulation of hormone secretion.

Decrease: cortisol by a negative feedback mechanism.

Mechanism of action

Cytosolic.

Targets and Effects

Targets are lymphoid , epithelial (mucous membranes and skin), adipose , bone and muscle tissue, liver .

Protein metabolism

• significant increase protein catabolism in lymphoid, epithelial, muscle, connective and bone tissues,
• in liver generally stimulates protein anabolism (for example, enzymes of transamination and gluconeogenesis),
• stimulation of transamination reactions through the synthesis of aminotransferases , which ensure the removal of amino groups from amino acids and the production of a carbon skeleton of keto acids,

Carbohydrate exchange

Generally cause an increase in blood glucose concentration:

• Increase in the power of gluconeogenesis from keto acids (derived from amino acids) by increasing the synthesis of phosphoenolpyruvate carboxykinase ,
• Increase in the synthesis of glycogen in the liver due to the activation of phosphatases and dephosphorylation of glycogen synthase .
• decrease of membrane permeability for glucose in insulin-dependent tissues.

Lipid exchange

• Stimulation of lipolysis in adipose tissue due to an increase in the synthesis of TAG-lipase , which enhances the effect of ACTH, STH, glucagon, catecholamines, i.e. cortisol has a permissive effect (English permission – permission).

Water-electrolyte exchange

Anti-inflammatory and immunosuppressive action

• Increased movement of lymphocytes, monocytes, eosinophils and basophils into lymphoid tissue,
• increase in the level of leukocytes in the blood due to their release from the bone marrow and tissues,
• suppression of the functions of leukocytes and tissue macrophages through reduction of synthesis of eicosanoids by reducing the transcription of enzymes phospholipase A ₂ and cyclooxygenase .

Other effects

Increases the sensitivity of the bronchi and blood vessels to catecholamines, which ensures the normal functioning of the cardiovascular and bronchopulmonary systems.

Inactivation of cortisol

Deactivation of cortisol, like other steroid hormones, occurs in the liver . The essence of the reactions is

• in the reduction of the double bond in the A-ring and the oxo group in the 3-position,
• in the elimination of the radical from the 17th carbon atom,
• in the conjugation of OH groups with sulfuric or glucuronic acids to form hydrophilic compounds.

As a result of deactivation, a variety of compounds are formed with sharply reduced hormonal activity or completely devoid of it.

Pathology

Hypofunction

The cause of primary insufficiency (Addison’s disease, bronze disease) is the destruction of the adrenal cortex during hemorrhage or trauma, autoimmune processes, tuberculosis, hemochromatosis. Hypocorticism is manifested as:

• hypoglycemia,
• hypersensitivity to insulin,
• anorexia and weight loss,
• weakness,
• hypotension,
• hyponatremia and hyperkalemia,
• increased pigmentation of the skin and mucous membranes (compensatory increase in the amount of ACTH, which has a slight melanotropic effect).

Secondary insufficiency occurs with ACTH deficiency or a decrease in its effect on the adrenal glands – all symptoms of hypocorticism occur, except for pigmentation.

Hyperfunction

Primary hyperfunction (Cushing’s syndrome, hypercortisolism syndrome, steroidal diabetes ) occurs in benign or malignant tumors of the adrenal cortex. It manifests itself as:

• decreased glucose tolerance – abnormal hyperglycemia after sugar load or after eating,
• hyperglycemia due to activation of gluconeogenesis,
• obesity of the face and trunk (associated with an increased effect of insulin in hyperglycemia on adipose tissue) – buffalo hump, apron (frog) belly, moon-shaped face,
• glucosuria,
• increase in protein catabolism and increase in blood nitrogen,
• osteoporosis and increased loss of calcium and phosphate from bone tissue,
• decrease in cell growth and division – leukopenia, immunodeficiencies, thinning of the skin, gastric ulcer and duodenal ulcer,
• violation of the synthesis of collagen and glycosaminoglycans,
• hypertension due to activation of the renin-angiotensin system.