11β-Hydroxytestosterone is an

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

, a

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

. Although it may not have significant androgenic activity, it may still be an important precursor to androgenic molecules.

Chemical properties

11β-Hydroxytestosterone is an androstanoid with the molecular formula C19H28O3 and a molecular weight of 304.42 Da. Its IUPAC name is (8S,9S,10R,11S,13S,14S,17S)-11,17-dihydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta henanthren-3-one, reflecting its steroid structure with hydroxyl groups at the 11β and 17β positions and a 3-keto group on the A-ring. The compound is a 3-oxo-Δ4 steroid, structurally related to testosterone, with an additional hydroxyl group at the 11β-position, which reduces its androgenic potency but enables further metabolism into active androgens. It is moderately soluble in water due to its hydroxyl groups but more soluble in organic solvents like ethanol.

Biosynthesis and metabolism

11β-Hydroxytestosterone is biosynthesized in the adrenal glands, primarily in the zona reticularis, through the action of cytochrome P450 11β-hydroxylase (CYP11B1), which catalyzes the hydroxylation of testosterone at the 11β-position. This enzyme, encoded by the CYP11B1 gene, is a mitochondrial P450 monooxygenase that also converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone, with weaker activity on testosterone. The reaction requires electron transfer from NADPH via adrenodoxin reductase and adrenodoxin, similar to other P450 systems. In adrenal tissue, testosterone, derived from androstenedione via

17β-hydroxysteroid dehydrogenase A hydroxysteroid is a molecule derived from a steroid with a hydrogen replaced with a hydroxy group. When the hydroxy group is specifically at the C3 position, hydroxysteroids are referred to as sterols, with an example being cholesterol ...

(17βHSD), serves as the precursor. Studies from the 1960s confirmed its production in human adrenal homogenates, with 11β-Hydroxytestosterone as the predominant metabolite of testosterone, alongside minor amounts of 11β-hydroxyandrostenedione (11OHA4) and

11-ketoandrostenedione Adrenosterone, also known as Reichstein's substance G , as well as 11-ketoandrostenedione (11-KA4), 11-oxoandrostenedione (11-OXO), and androst-4-ene-3,11,17-trione, is a steroid hormone with an extremely weak androgenic effect, and an intermedia ...

(11KA4). Its biosynthesis is regulated by adrenocorticotropic hormone (ACTH), which upregulates CYP11B1 expression. In peripheral tissues, 11β-Hydroxytestosterone is metabolized by

11β-hydroxysteroid dehydrogenase type 2 Corticosteroid 11-β-dehydrogenase isozyme 2 also known as 11-β-hydroxysteroid dehydrogenase 2 is an enzyme that in humans is encoded by the gene. Function Corticosteroid 11-β-dehydrogenase isozyme 2 is an NAD+-dependent enzyme expressed in ...

(11βHSD2) to 11-ketotestosterone (11-KT), a more potent androgen, or by 5α-reductase to 11β-hydroxydihydrotestosterone (11OHDHT), both of which are androgen receptor (AR) agonists.

Biological role

11β-Hydroxytestosterone has weak androgenic activity compared to testosterone or

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...

(DHT) due to the 11β-hydroxyl group, which reduces its affinity for the androgen receptor. However, it is a critical precursor in the C11-oxy C19 steroid pathway, which produces potent androgens like 11-KT and 11-KDHT, particularly in peripheral tissues such as the prostate. This pathway challenges the traditional view that testosterone and DHT are the sole potent androgens in humans.

Clinical relevance

* Polycystic Ovary Syndrome (PCOS): 11β-Hydroxytestosterone levels are elevated in PCOS patients, often exceeding testosterone levels, making it a potential biomarker for hyperandrogenism. * Castration-Resistant Prostate Cancer (CRPC): The C11-oxy C19 pathway, including 11β-Hydroxytestosterone, contributes to androgen production in CRPC, where adrenal-derived 11OHA4 and 11OHT are metabolized to 11-KT and 11-KDHT in prostate tissue, sustaining tumor growth despite androgen deprivation therapy. * Congenital Adrenal Hyperplasia (CAH): Mutations in the CYP11B1 gene, which encodes 11β-hydroxylase, can lead to 11β-hydroxylase deficiency, increasing 11β-Hydroxytestosterone precursors like testosterone and androstenedione, contributing to virilization.

Research

Recent research has focused on the C11-oxy C19 steroid pathway, with 11β-Hydroxytestosterone identified as a key intermediate. A 2013 study in LNCaP prostate cancer cells demonstrated its conversion to 11-KT and 11-KDHT, highlighting its role in CRPC. A 2016 study confirmed its elevated levels in 21-hydroxylase deficiency, another form of CAH, where it contributes to adrenal androgen excess.

Detection in doping and testing

Given its anabolic properties, 11β-Hydroxytestosterone is monitored in anti-doping testing. It can be detected in urine samples as part of testing for banned substances. Its detection helps identify the misuse of testosterone or other anabolic steroids, as athletes may attempt to mask their use of these substances by metabolizing testosterone into 11β-hydroxytestosterone. Specialized tests are used to measure the ratio of 11β-Hydroxytestosterone to testosterone, as a way to flag illicit use of exogenous substances.

References

Androstanes Human metabolites {{steroid-stub