11-Hydroxy-Androsterone

11-Hydroxyandrosterone, a less commonly discussed but significant androgen, represents a unique aspect of adrenal steroid metabolism. 

This compound belongs to the broader family of 11-oxygenated androgens, which are adrenal-derived C19 steroids that have recently been recognized for their role in various physiological and pathological states in humans. 

Traditionally overshadowed by more well-known androgens like testosterone and dihydrotestosterone, 11-hydroxyandrosterone and its counterparts such as 11-ketotestosterone are redefining our understanding of androgen activity, especially in conditions like congenital adrenal hyperplasia, polycystic ovary syndrome, and Cushing's syndrome. 

As we delve deeper into their functions and implications, 11-oxyandrogens are becoming recognized not just as biochemical curiosities but as pivotal components of our endocrine system, influencing a range of physiological processes and disease states.

This article aims to explore the biosynthesis, function, and clinical significance of 11-hydroxyandrosterone, shedding light on its pivotal roles in the body and its potential implications in medical science.

Understanding 11-Hydroxy-Androsterone

Definition: What is 11-Hydroxy-Androsterone?  [4.] 

11-hydroxy androgens, particularly 11-hydroxyandrosterone, represent a class of adrenal-derived C19 steroids that include both potent androgens and inactive precursors. 

Traditionally overshadowed by testosterone and 5α-dihydrotestosterone, recent discoveries highlight the significance of 11-oxygenated androgens such as 11-ketotestosterone in human physiology, expanding our understanding of the androgen pool, especially in women. 

These androgens are synthesized primarily in the adrenal cortex through the action of cytochrome P450 11β-hydroxylase (CYP11B1) and contribute to various conditions including congenital adrenal hyperplasia, polycystic ovary syndrome, and Cushing's syndrome. 

Peripheral tissues play a key role in converting the circulating precursor 11β-hydroxyandrostenedione (11OHA4) into active androgens like 11-ketotestosterone. This process is influenced by factors such as body mass index (BMI) and insulin resistance, highlighting the metabolic significance of 11-oxygenated androgens. 

These findings challenge long-held views and underscore the complexity and importance of these androgens in health and disease.

Physiological Roles of 11-Hydroxy-Androsterone

Despite being a minor metabolite, 11-Hydroxy-Androsterone plays essential roles in various physiological processes. 

11-Hydroxy-Androsterone promotes the development of masculine characteristics, and shows profound effects on scalp and body hair in humans.  [2.]

Unlike traditional androgens, 11-oxyandrogens do not show an age-related decline in concentration, indicating their continuous relevance across the human lifespan.  [5.]

This insight has sparked a broader reevaluation of their roles, particularly in conditions characterized by androgen excess such as congenital adrenal hyperplasia, premature adrenarche, polycystic ovary syndrome, and even in the androgen-dependent dynamics of castration-resistant prostate cancer. 

Production of 11-Hydroxy-Androsterone and other 11-Hydroxy-Androgens  [3.] 

The production of 11-oxyandrogens is primarily mediated by the adrenal enzyme cytochrome P450 11β-hydroxylase (CYP11B1), which is abundantly expressed in the zona fasciculata and zona reticularis of the adrenal gland. 

This enzyme catalyzes the last step in cortisol synthesis under the influence of adrenocorticotropic hormone (ACTH) and also converts androstenedione (A4) and testosterone (T) into 11β-hydroxyandrostenedione (11OHA4) and 11β-hydroxytestosterone (11OHT), respectively.  These can both be converted into 11-hydroxy-androsterone.   

While 11β-hydroxyandrostenedione can also be synthesized from cortisol, this is a less significant pathway. 

Both 11OHA4 and 11OHT are further metabolized by 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) into their respective ketosteroids, 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT), processes occurring in both the adrenal gland and peripheral tissues. 

Additionally, 11KT can be formed by the reduction of 11KA4, facilitated by aldo-keto reductase 1C3 (AKR1C3) or 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5). Moreover, 11-ketodihydrotestosterone (11KDHT) can be produced from 11β-hydroxydihydrotestosterone (11OHDHT) through 11βHSD2, or from 11-keto-5α-androstanedione (11KDHA4) via AKR1C3.

Laboratory Testing for 11-Hydroxy-Androsterone

Laboratory Test Information, Sample Collection and Preparation

Laboratory assessment of 11-Hydroxy-Androsterone is typically accomplished via urine.  A 24-hour urine collection may be recommended or required.  

It is essential to consult with the ordering healthcare provider prior to sample collection, as alterations in medication use may be recommended.  

Interpretation of 11-Hydroxy-Androsterone Results

Reference Range for 11-Hydroxy-Androsterone Testing

It is recommended to consult with the laboratory company used to interpret test results.  A reference range for urine 11-hydroxy-androsterone over 24 hours is:  [1.] 

Women 18-49 years: 59-12,462 mcg/24 hour

Women 50 years and older: 86-9,280 mcg/24 hour 

Men 18-49 years: 108-11,987 mcg/24 hour

Men 50 years and older: 142-13,135 mcg/24 hour

Clinical Significance of Elevated 11-Hydroxy-Androsterone Levels

Causes of increased 11-hydroxy-androsterone levels can include:

Congenital adrenal hyperplasia (CAH): specifically, forms like 21-hydroxylase deficiency which leads to increased production of adrenal androgens.  [3.] 

Adrenal tumors: tumors or hyperplasia in the adrenal glands can lead to excessive production of androgens including 11-hydroxyandrosterone.  [1.] 

Adrenal enzyme overactivity: increased activity of enzymes such as CYP11B1, which is involved in the synthesis of 11-hydroxyandrosterone from precursors like androstenedione and 21-deoxycortisol.  [5.] 

Polycystic ovary syndrome (PCOS): although primarily associated with ovarian androgen excess, PCOS may also involve adrenal contributions to elevated androgen levels.  [1.] 

Endocrine disorders: Other disorders that dysregulate the hormonal balance, leading to increased adrenal androgen production.

Clinical Significance of Low Levels of 11-Hydroxy-Androsterone

Low levels of 11-hydroxy-androsterone may not be considered clinically relevant.  However, in the presence of symptoms of androgen deficiency, low levels of 11-hydroxy-androsterone may signal an androgen deficiency.    ‌

Testing Biomarkers Related to 11-Hydroxy-Androsterone

Understanding related biomarkers alongside 11-Hydroxy-Androsterone can offer a more comprehensive assessment of adrenal health and hormonal balance.

Cortisol

Cortisol, often referred to as the "stress hormone," is a key steroid hormone produced by the adrenal glands. It plays essential roles in regulating metabolism, immune function, and stress responses. 

Measurement of cortisol levels in serum or saliva is commonly used to assess adrenal function and diagnose conditions such as adrenal insufficiency, Cushing's syndrome, and adrenal tumors. 

Cortisol testing may complement 11-Hydroxy-Androsterone measurements in evaluating adrenal steroidogenesis and identifying abnormalities in cortisol metabolism.

Dehydroepiandrosterone (DHEA)

Dehydroepiandrosterone (DHEA) is a precursor hormone synthesized by the adrenal glands and gonads. It serves as a substrate for the production of androgens and estrogens, playing a role in sexual development, mood regulation, and immune function. 

Measurement of DHEA levels in serum or saliva can provide insights into adrenal function and hormonal balance. Alterations in DHEA levels may indicate adrenal dysfunction, aging-related changes, or metabolic disorders. 

Assessing DHEA levels alongside 11-Hydroxy-Androsterone can enhance the evaluation of adrenal steroidogenesis and hormonal status.

Androstenedione

Androstenedione is an androgenic steroid hormone synthesized in the adrenal glands and gonads. It serves as a precursor for testosterone and estrone, contributing to the androgenic and estrogenic pathways. 

Measurement of androstenedione levels in serum or urine can aid in assessing adrenal and gonadal function and diagnosing conditions such as adrenal tumors, polycystic ovary syndrome (PCOS), and congenital adrenal hyperplasia (CAH). 

Monitoring androstenedione levels alongside 11-Hydroxy-Androsterone may provide additional insights into adrenal steroidogenesis and androgen metabolism.

Aldosterone

Aldosterone is a mineralocorticoid hormone synthesized by the adrenal cortex, primarily in response to changes in blood pressure, sodium, and potassium levels. It plays a crucial role in regulating electrolyte balance, blood volume, and blood pressure. 

Measurement of aldosterone levels in serum or urine is used to evaluate adrenal function and diagnose conditions such as primary aldosteronism (Conn's syndrome), adrenal hyperplasia, and adrenal tumors. 

Assessing aldosterone levels alongside 11-Hydroxy-Androsterone can help assess adrenal steroidogenesis and mineralocorticoid activity, particularly in the context of adrenal disorders and hypertension.

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