Disorders of Androgen Biosynthesis

Written by Ben Bunting: BA, PGCert. (Sport & Exercise Nutrition) // British Army Physical Training Instructor // S&C Coach.


Diseases caused by abnormalities in androgen biosynthesis

In males, the androgen receptor and its signaling pathway are involved in male sexual differentiation.

Abnormalities in this pathway have been linked to a number of diseases, including androgen insensitivity syndrome, spinal bulbar muscular atrophy, and prostate cancer.

These diseases can lead to a wide variety of symptoms, including fatigue, depression, and low sex drive.

Androgen biosynthesis is impaired by a variety of genetic abnormalities. In some cases, a critical enzyme is deleted or mutated, causing the body to produce insufficient amounts of androgens.

In addition, there are enzymatic deficiencies that occur at any point in the biosynthesis of androgens.

These enzymatic deficiencies lead to deficient androgen production and buildup of precursors. In some cases, these disorders result in distinct clinical syndromes.

A person with androgen insensitivity syndrome is genetically male, but has a male penis and internal female characteristics and thus are sexually ambiguous.

The penis may be small and unformed or the genitals may be a mix of male and female. In addition, the person has a small risk of developing a cancer later in life.

Androgen synthesis in the gonads requires cholesterol, which is the primary substrate. The mitochondria of the adrenals, ovarian stroma, and placenta convert cholesterol to pregnenolone.

The conversion is performed by the mitochondrial cytochrochromonase complex. The luteinizing hormone helps regulate the process.

Disorders of androgen biosynthesis can cause diseases in the body, such as hirsutism.

Most of these disorders are rare, and the proper treatment consists of medication for suppressing androgen secretion and counteracting the effects of these androgens.

Patients with hyperandrogenism should also undergo an ovarian sonography to rule out a hormonal disorder.

Most 46,XY infants with abnormal testosterone synthesis will be raised as females.

Treatment for severe hypospadias may include orchiectomy, which eliminates the intra-abdominal testes and prevents potential virilization at puberty.

In milder cases, a patient may be raised as a male after reconstructive surgery, and androgens can be used to induce sexual maturation.

Some treatments that block androgen biosynthesis include androgen receptor signaling inhibitors, or ARSIs.

These drugs target androgen receptor signaling and attenuate the adaptive responses to ADT. There are two main classes of these drugs: potent AR antagonists, such as enzalutamide, and P450c17 inhibitors, such as abiraterone acetate.

Both classes of ARSIs can improve overall survival, but some patients may develop drug resistance.

Treatment options

Disorders of androgen biosynthesis can result in a variety of issues, from acne to polycystic ovary syndrome (PCOS).

Women with polycystic ovary syndrome have irregular or absent menstrual periods, blood sugar disorders, and prediabetes.

Treatment for these conditions depends on the type of ailment.

Treatment for disorders of androgen biosynthesis can include prescription hormones such as testosterone and progestin. It may also include birth control pills that contain estrogen.

Oral estrogens may help to reduce the levels of free testosterone, which triggers symptoms. Other medications such as glucocorticoids may also be used to suppress androgen production.

Initial diagnostic information about the condition comes from a woman's medical history and physical examination.

A physician may also perform laboratory tests to confirm the presence of hyperandrogenism. These tests will measure levels of free testosterone, total testosterone, and cholesterol in the blood.

Other tests may include a lipid profile and blood glucose levels. Endocrine function tests may also be performed to determine the site of abnormal androgen secretion.

Low androgen levels can cause decreased libido and low sexual desire. Other symptoms may include fatigue and reduced well-being.

Additionally, low androgen levels are associated with osteoporosis, a condition in which bones become thin and brittle.

Ovarian failure and surgical removal of the ovaries may also contribute to osteoporosis.

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Genetic testing

Genetic testing for disorders of androgen biosynthetic pathways can confirm or deny a condition.

This test uses mutational analysis to detect a particular gene, which is usually a gene encoding the androgen receptor.

The androgen receptor gene is located on chromosome Xq11-12, and it codes for a protein that has three major functional domains. This gene belongs to the nuclear receptor superfamily and has over one thousand mutations.

The tests are performed by multiplex ligation-dependent probe amplification, which can detect deletions and duplications of exons.

AR gene mutations are rare, but a small number of deletions have been identified. Many of these deletions are nonfunctional.

Despite the rarity of these cases, AR mutations can lead to the development of diseases such as Kennedy disease, which is characterized by a polyglutamine tract expansion.

Androgen insensitivity is inherited X-linked. A child with complete androgen insensitivity will have a shallow vagina, a sign of incomplete mullerian development.

This condition is often accompanied by inguinal hernias. Occasionally, androgen insensitivity can be detected during a gynecological operation.

Genetic testing for disorders of androgen biosynthetic activity (AR) may include single gene testing or multigene panels.

The sensitivity of these tests is likely to change over time, but a multigene panel that includes a wide range of genes can help confirm the diagnosis.

Affected individuals can also have a hemizygynous or XY karyotype. If a sibling is asymptomatic carrier, an AR gene analysis may be performed to determine the genetic disorder. A patient may also need to undergo androgen binding assays.

Genetic testing for disorders of androgen biosynthetic pathway is a valuable way to diagnose a disease.

It enables a doctor to determine the cause of the disorder and recommend preventive measures for family members. It also allows for early detection, which can improve prognosis.

Earlier detection of the disorder may prevent cancer. Patients with CAIS are at high risk for developing tumors, particularly gonadoblastomas.

In cases where tumors are present, surgical treatment may be recommended. The incidence of tumors associated with this disease ranges between 1.5-2 percent of undescended testes.


Androgen biosynthesis disorders are genetic syndromes characterized by excessive production of androgens in the body.

While they are uncommon causes of sexual ambiguity in 46,XY males, they are common causes of virilization in 46,XX females.

To understand these disorders, one must understand the steroidogenic pathways that regulate androgen synthesis.

These pathways are composed of steroidogenic acute regulatory protein (Srp), which is required for androgen biosynthesis, and steroidogenic enzymes. Insufficient levels of either protein or enzyme can result in excess production of androgens.

Genetic studies of the syndromes have shown that most of these disorders are caused by variations in one or more genes.

As a result, advances in molecular genetics have improved the ability to diagnose these disorders and provide information about the prognosis and risk for gonadal malignancies.

Genetic diagnosis of these conditions can alleviate the stigma and anxiety associated with the disorder, and is an important tool in treatment planning.

Some of these conditions are related to the androgen receptor gene, which is located on the X chromosome.

This gene is responsible for controlling the production of androgen in the body. If the affected gene is not functioning properly, then the affected individual may develop hypospadias.

This is a condition in which the penis fails to develop properly or does not grow at all.

This disorder disrupts dehydroepiandrosterone biosynthesis in the human fetus, which is essential for external genital differentiation.

Dehydroepiandrosterone biosynthetic failure results in congenital adrenal hyperplasia. In girls with this condition, the hormone dehydroepiandrosterone is not converted to 5a-dihydrotestosterone.

As a result, the body accumulates 17a-hydroxyprogesterone. 


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