What is the Late-Onset AGS?
You are already familiar with various conditions affecting the uterus and its adjacent structures and associated symptoms. This article focuses on a hormonal disorder known as late-onset adrenogenital syndrome (AGS). This condition can lead to issues such as infertility, typically amenable to treatment.
The Adrenal Gland
The adrenal gland, also known as the suprarenal gland, is a small triangular-shaped gland and a vital component of the endocrine system. Positioned atop each kidney, these paired glands play a significant role in producing stress hormones in response to various environmental triggers that demand enhanced bodily performance. Additionally, they secrete hormones responsible for regulating water and salt balance, metabolism, and the immune system.
Structure and Functions of the Adrenal Gland
The adrenal gland is structurally divided into the outer adrenal cortex and the inner adrenal medulla. The adrenal cortex produces hormones such as aldosterone, cortisol, and androgens, which are male sex hormones. Cortisol particularly affects metabolism by promoting the breakdown of fats and proteins and increasing sugar production. Prolonged elevated cortisol levels can lead to higher blood sugar, especially under chronic stress. This hormone also has anti-inflammatory properties and inhibits immune system activity. Aldosterone primarily regulates salt and water balance by controlling sodium and potassium levels, and crucial electrolytes essential for various bodily processes. In cases of low blood pressure, aldosterone prompts the kidneys to retain sodium and water. Androgens are transformed into testosterone, with males having higher testosterone levels than females*. However, the adrenal gland contributes only a small portion of testosterone in men*, while the bulk is produced by the testes.
Hormone Production in the Adrenal Gland
Typically, the pituitary gland in the brain oversees hormone production by the adrenal cortex. This, in turn, is regulated by the hypothalamus, another brain region. The process involves stimulation from the pituitary gland to increase hormone production when required. Conversely, production is curtailed when hormone levels are sufficient.
Hormone production can be disrupted by conditions like tumors, leading to overactivity or underactivity of the adrenal cortex. Excessive cortisol secretion results in Cushing’s disease, characterized by a rounded face, abdominal fat accumulation, and potential diabetes. Overproduction of aldosterone causes high blood pressure and low potassium levels, manifesting as muscle weakness, constipation, and thirst. Inadequate hormone production triggers adrenal insufficiency, known as Addison’s disease. Changes in the hypothalamus or pituitary gland can also lead to underactivity. Insufficient cortisol production may cause weight loss, low blood pressure, loss of appetite, and menstrual irregularities. Symptoms may not appear until heightened stress necessitates more cortisol, which the body cannot produce, leading to a life-threatening condition called Addisonian crisis.
The adrenal medulla generates stress hormones like adrenaline, noradrenaline, and dopamine, collectively known as catecholamines. It forms part of the sympathetic nervous system, responsible for the body’s heightened state of readiness. These hormones elevate blood pressure, heart rate, and blood sugar levels, and inhibit intestinal activity. Overactivity of the adrenal medulla can cause sudden high blood pressure, accompanied by headaches, dizziness, and sweating. If the adrenal medulla does not produce enough catecholamines, it is called hypofunction. Insufficient catecholamine production results in low blood pressure, causing symptoms like dizziness, fainting, and headaches ,,.
What is Adrenogenital Syndrome?
In classic adrenogenital syndrome, an underproduction of cortisol and aldosterone occurs, while at the same time, an excess of androgens is produced. This often arises from a genetic alteration in an enzyme crucial for hormone production, most commonly affecting the 21-hydroxylase enzyme. Due to this enzyme deficiency, insufficient cortisol and aldosterone are produced from cholesterol, leading to chronically low levels of these hormones. In response, the production of ACTH (adrenocorticotropin) increases, causing the adrenal cortex to enlarge. Despite the enzyme defect, the hormone precursors are redirected towards androgen production instead of cortisol and aldosterone, resulting in an excess of male sex hormones.
In girls*, this deficiency manifests as masculinization of the vulva, which occurs before birth. It leads to an enlarged clitoris and altered labia majora, resulting in the development of intersex organs. However, this only affects the external genitalia; the internal sex organs remain normal and functional. In boys*, there are usually subtle signs like a slightly enlarged penis and darker scrotum. After a few days, depending on the severity, salt loss, and increased potassium levels can occur due to the aldosterone deficiency, leading to weight loss and weakness. These symptoms can be life-threatening. If undiagnosed, affected girls* might also experience salt wasting.
Non-classical or late-onset adrenogenital syndrome involves a milder alteration of the enzyme, initially showing no apparent signs. However, during childhood and adolescence, girls* may experience increased growth, acne, excessive hairiness, and early pubic hair. Adult women* with this condition might develop irregular menstrual cycles, potentially leading to fertility issues. Boys* and men* typically do not exhibit symptoms ,,.
How is AGS diagnosed?
In the classic form, the noticeable changes in girls* often lead to an immediate diagnosis, usually through a blood test. Diagnosing boys*, however, is more challenging due to the absence of obvious changes. Given the life-threatening nature of the condition, many European countries include newborn screening that tests for genetic alterations in the enzyme responsible for AGS, 21-hydroxylase. This approach allows for early detection and treatment of the disease.
For late-onset AGS, screening is also a viable diagnostic method. If screening is not conducted, diagnosis may occur when investigating the causes of infertility later in life or when other symptoms arise ,.
How is AGS Treated?
The treatment approach for both AGS and late-onset AGS involves similar drug therapies. The missing hormones must be supplemented through lifelong medication. Typically, oral tablets are taken two to three times a day. It is crucial to adjust the medication dosage in response to additional stressors like infections, surgeries, or accidents, to meet the body’s increased hormone requirements.
Treatment for Children
In girls* with AGS, surgery on the external genitalia has traditionally been performed between 2 and 6 months of age in specialized centers, depending on the severity of the condition. The goal is to ensure normal genital function in the future. The procedure involves reducing the size of the clitoris and separating fused labia. In some cases, correction of the vaginal opening is also necessary. However, ethical debates have arisen around these surgeries, as intersex genitalia are essentially present, and the child cannot provide consent for potential sex reassignment procedures later in life. Some argue for leaving the vulva untouched and deferring the decision to the individual when they are older. The decision to proceed with surgery or not should be carefully discussed with the medical team, considering individual benefits and risks .
Treatment for Adults
In adults, although internal reproductive organs are typically unaffected, fertility might be compromised based on disease severity. Late-onset AGS can remain asymptomatic for a long time, leading to delayed detection. If fertility is reduced and late-onset AGS is diagnosed, treatment is still possible. If pregnancy is challenging, it is advisable to consult an endocrinologist* to optimally regulate hormone supplementation through medication. The physician should also provide guidance during pregnancy to maintain proper hormonal balance. As AGS is a genetic condition, it is likely that the unborn child will also be affected. Monitoring hormones during pregnancy is vital to minimize masculinization of the genitals in the child. Administering hormones to fetuses without deficiencies can result in severe side effects and deformities. Therefore, hormone therapy should be carefully considered, weighing the benefits against the risks. Hormone supplementation aims to counter the excess production of androgens by providing the missing hormones. Once the child’s sex is unequivocally determined and if it is a boy*, no further therapy is needed. If the child presents with female sexual characteristics, AGS testing should be conducted. If no indications of AGS are found, therapy is discontinued immediately. Otherwise, medication is continued until birth ,.
In a Nutshell
As you see, AGS is highly treatable, and it certainly does not signify an inability to have children. If you suspect that you might have the condition, it is imperative to seek testing without delay. This is particularly crucial if you are nurturing an unfulfilled desire to start a family. Should your suspicion be confirmed, seeking consultation and treatment from an endocrinologist* is strongly recommended.
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