What is Adrenogenital Syndrome?

In this section you will learn the most important facts about AGS. AGS is a congenital hormonal disorder of the adrenal glands. There are different forms and degrees of severity of AGS – for example, with or without salt wasting. AGS can occur in all genders. In girls, it can lead to so-called masculinization of the external genitalia. Today, AGS is not without risks, but it can be well managed throughout life with medication in tablet form.

The diagnosis of AGS covers various disorders of the adrenal gland, all of which lead to a reduced production of cortisol. This reduced production is caused by an enzyme defect.

Enzymes are proteins that, in the case of the adrenal gland, are involved in the production of signaling substances (hormones). Thus, the diagnosis of AGS belongs to a group of diseases also referred to as “congenital adrenal insufficiency.” Insufficiency means that the adrenal gland is underfunctioning.

The adrenal gland is a hormone gland that sits like a small cap on the kidney and produces various vital signaling substances, also known as hormones. These include, first, glucocorticoids, which are essential for coping with stress situations. Second, there are mineralocorticoids, which are necessary for maintaining the body’s salt-water balance.

Third, androgens are important for muscle strength in both men and women but can lead to a masculinized appearance if overproduced.

In AGS, the production of these adrenal signaling substances is altered, in other words, “insufficient.” Glucocorticoids and mineralocorticoids are produced in too low amounts in the adrenal gland, while too many androgens are produced at the same time. As a result, the adrenal gland enlarges because it attempts to compensate for the lack of hormone production through cell growth.

This is why the condition is also referred to in English as congenital adrenal hyperplasia (CAH). In about 90% of people affected by AGS, the enzyme defect is a so-called “21-hydroxylase deficiency.”

Depending on the severity of the enzyme defect in the infant, either the full manifestation of the disease occurs – also referred to as “classical AGS” or “early onset AGS” – or a milder form of the disease. The latter is referred to as “non-classical AGS” or “late-onset AGS.”

While the residual activity of the 21-hydroxylase enzyme in classical AGS is usually between 0% and 5%, in non-classical AGS it still ranges from about 20% to a maximum of 50%. Within classical AGS, one can further distinguish between AGS with salt wasting (75%–90%) and AGS without salt wasting (0%–25%).

In addition to classical and non-classical AGS, there are other rare forms of adrenogenital syndrome,

AGS due to 11β-hydroxylase deficiency
AGS due to 3β-hydroxysteroid dehydrogenase deficiency
AGS due to 17α-hydroxylase deficiency
AGS due to StAR deficiency

which differ not only genetically but also in their clinical presentation.

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Here we would like to give you the opportunity to download the brochure of the AGS Initiative e.V. This comprehensive brochure includes, in addition to the topics covered on our website, further information such as family planning and fertility. A special chapter is dedicated to the formal and bureaucratic aspects related to Adrenogenital Syndrome (AGS).

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Hormone production in the healthy adrenal gland

In a healthy adrenal gland, there are three production or synthesis pathways for hormones, which usually function smoothly without any blockages. There are no “obstacles” for the substances, which move like small cars on open roads and later combine to form vital hormones. These “production roads” normally enable the formation of the salt-regulating hormone “aldosterone,” the stress hormone “cortisol,” and the “androgens” as male hormones. Ideally, these three classes of substances are produced without disruption and in sufficient quantities.

In the healthy adrenal cortex, three different classes of signaling substances (hormones) are produced:

Glucocorticoids: Cortisol
Mineralocorticoids: Aldosterone
Androgens: Testosterone and testosterone precursors

Glucocorticoids

You are probably familiar with the word stems “gluco” (meaning sugar) and “cortex” (meaning here from the cortex, specifically the adrenal cortex). The most important and best-known representative of the so-called glucocorticoids is the body’s own vital stress hormone “cortisol.” On the one hand, it is responsible for stabilizing blood sugar – hence the word stem “gluco.” On the other hand, cortisol is increasingly needed during physical stress, such as acute illness with fever, severe accidents, or surgery, in order to control the extent of inflammatory or stress reactions in the body.

Through its blood sugar–stabilizing effect, cortisol releases glucose, which is an important energy source for the body. This keeps blood sugar levels constant even during fasting, which is particularly important in stressful situations. Cortisol must also be present in the blood for the hormone “adrenaline” to take effect. In addition, it plays an important role in ensuring a healthy immune and inflammatory response.

Mineralocorticoids

You are probably already familiar with the word “minerals” and associate it with the idea of “salts.” The so-called “mineralocorticoids” are hormones that regulate the salt balance in human blood as well as the body’s fluid balance.

The most important mineralocorticoid is “aldosterone.” It ensures that enough salt in the form of sodium chloride is retained in the body and not immediately excreted through the kidneys. At the same time, it promotes the excretion of another important blood salt, potassium. Along with salt, water is also retained in the human body – which helps maintain a healthy, age-appropriate blood pressure. However, if the body produces too little aldosterone, it increasingly loses salt and water, blood pressure drops, and this can result in a “salt-wasting crisis.” In such a case, the concentration of potassium can rise so much that cardiac arrhythmias and, in the worst case, cardiac arrest may occur.

Androgens

Almost everyone knows the word “testosterone” and quickly associates it with large, strong, and hairy men. Testosterone is the best-known representative of the so-called “androgens,” which are also referred to as sex hormones. Regardless of gender, these androgens lead to hair growth, muscle development, and a deep voice.

If an adult woman has too many androgens in her body, this usually results in excessive and often unpleasant hair growth in a male pattern – medically referred to as “hirsutism.”

In addition, menstrual irregularities and a generally masculinized appearance may occur.

Information for all age groups

Our website provides comprehensive information on AGS in newborns, children, adolescents, and young adults. No matter which age group you belong to, you will find reliable information on diagnostic procedures, medical aspects, treatment options, family planning, psychosocial support, and many other relevant topics.

Infancy Childhood Adolescents (young) adults

What happens in AGS?

In AGS, a genetically determined enzyme deficiency leads to a disruption of hormone production in the human adrenal cortex. Normally, various enzymes build glucocorticoids (cortisol), androgens (testosterone precursors), and mineralocorticoids (aldosterone) from a common precursor – cholesterol. If one of the important enzymes, called “21-hydroxylase,” is not sufficiently effective in AGS, the production chain is interrupted at this point. As a result, cortisol and aldosterone are not produced in sufficient quantities, while androgens are produced in excess. The pituitary gland recognizes that the cortisol level is too low and tries to stimulate the adrenal cortex to produce more cortisol through another signaling substance called “ACTH.” However, the hormone that lies beyond the enzyme block (cortisol and aldosterone) cannot increase. The high ACTH, however, stimulates the adrenal cortex to produce large amounts of androgens.

In AGS, the hereditary enzyme defect blocks the pathways to the stress hormone cortisol and to aldosterone, the hormone that regulates salt balance. Only the pathway to the androgens remains functional, which is why these are now increasingly produced in the adrenal gland.

The production of cortisol is centrally controlled in the brain, specifically by the hypothalamus in the diencephalon and the pituitary gland. This regulation is referred to as the “hypothalamic-pituitary-adrenal axis.” When the body detects that there is too little cortisol, feedback is sent to the hypothalamus and pituitary gland in the brain. The brain messengers from the hypothalamus, called “corticotropin-releasing hormone = CRH,” and from the pituitary gland, called “adrenocorticotropic hormone = ACTH,” are then released in greater quantities. ACTH additionally stimulates the adrenal cortex to produce all three of its signaling substances, including cortisol (see figure: What happens in AGS).

If cortisol concentration in the body is very high, the pituitary gland is signaled that enough hormones are present and that the release of ACTH and CRH can be stopped. This is also referred to as “negative feedback.” As a result, less CRH and ACTH are released, and the adrenal gland is less stimulated to produce cortisol. Due to the cortisol deficiency in AGS, more CRH and ACTH are secreted. This stimulates the adrenal gland to produce cortisol, which, however, is not possible due to the enzyme defect. The only product that the “AGS adrenal gland” can produce are androgens, whose production subsequently increases continuously and unchecked.

In AGS, the signaling substance aldosterone is also missing in addition to cortisol. As mentioned earlier, aldosterone is a mineralocorticoid and plays an important role in regulating the body’s salt-water balance. Mineralocorticoids ensure that enough salt in the form of sodium chloride is retained in the body and not excreted by the kidneys. If aldosterone is missing, AGS with salt wasting occurs, because without aldosterone the body cannot retain salt and excretes it rapidly and without restriction via the kidneys. At the same time, aldosterone promotes the excretion of another important blood salt, potassium. The absence of aldosterone leads to an increase in potassium in the blood. Too much potassium in the human body can cause life-threatening cardiac arrhythmias. Salt also retains water in the body, which in turn maintains blood pressure at a sufficient level. The production of mineralocorticoids is primarily regulated by its own system – the so-called “renin-angiotensin-aldosterone system.”

If the mineralocorticoid level drops, the concentration of renin and angiotensin in the blood rises. At the same time, more aldosterone is normally produced in the adrenal gland. If aldosterone is missing in AGS with salt wasting, renin from the kidney increases and more “angiotensinogen and angiotensin I + II” are formed. However, due to the enzyme defect, no aldosterone is produced. An elevated renin value measured in the blood is therefore an indication of a mineralocorticoid deficiency, specifically “aldosterone deficiency,” and thus points to AGS with salt wasting.

In summary, AGS results in the adrenal gland producing too little of the hormones cortisol and mineralocorticoids, and too many hormones in the form of androgens. In “21-hydroxylase deficiency,” one finds clinical symptoms of adrenal insufficiency and of excess male hormones. Due to the lack of cortisol, the body’s ability to adapt to stress situations (illness, infection, fever, surgery, severe pain) is reduced. The body with AGS produces too few mineralocorticoids. It loses salt and water, blood pressure drops, and untreated patients tend to develop a “salt-wasting crisis.” The concentration of potassium rises so sharply that, in the worst case, cardiac arrest may occur. This must be avoided by all – fortunately available – medical means.