Clinical significance of 11-oxygenated androgens

Turcu, Adina F.; Auchus, Richard J.

doi:10.1097/med.0000000000000334

Cited by 62 publications

(42 citation statements)

References 44 publications

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“…Our findings can serve as some guide for risk stratification in the situation of incidental androgen excess findings. In addition to the classic androgen synthesis pathway from DHEAS via A4 to T and DHT, recent studies have highlighted the significance of the 11-oxygenated androgen pathway ( 40 , 41 ). This is initiated by conversion of A4 to 11-hydroxyandrostenedione by adrenal CYP11B1, with further downstream activation to 11keto-testosterone and 11keto-dihydrotestosterone, which bind and activate the androgen receptor with similar affinity and potency as T and DHT.…”

Section: Discussionmentioning

confidence: 99%

Causes, Patterns, and Severity of Androgen Excess in 1205 Consecutively Recruited Women

Elhassan

Idkowiak

Smith

et al. 2018

The Journal of Clinical Endocrinology &Amp; Metabolism

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ContextAndrogen excess in women is predominantly due to underlying polycystic ovary syndrome (PCOS). However, there is a lack of clarity regarding patterns and severity of androgen excess that should be considered predictive of non-PCOS pathology.ObjectiveWe examined the diagnostic utility of simultaneous measurement of serum dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), and testosterone (T) to delineate biochemical signatures and cutoffs predictive of non-PCOS disorders in women with androgen excess.DesignRetrospective review of all women undergoing serum androgen measurement at a large tertiary referral center between 2012 and 2016. Serum A4 and T were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased serum androgen underwent phenotyping by clinical notes review.ResultsIn 1205 women, DHEAS, A4, and T were measured simultaneously. PCOS was the most common diagnosis in premenopausal (89%) and postmenopausal women (29%). A4 was increased in all adrenocortical carcinoma (ACC) cases (n = 15) and T in all ovarian hyperthecosis (OHT) cases (n = 7); all but one case of congenital adrenal hyperplasia (CAH; n = 18) were identified by increased levels of A4 and/or T. In premenopausal women, CAH was a prevalent cause of severe A4 (59%) and T (43%) excess; severe DHEAS excess was predominantly due to PCOS (80%). In postmenopausal women, all cases of severe DHEAS and A4 excess were caused by ACC and severe T excess equally by ACC and OHT.ConclusionsPattern and severity of androgen excess are important predictors of non-PCOS pathology and may be used to guide further investigations as appropriate.

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Section: Discussionmentioning

confidence: 99%

Causes, Patterns, and Severity of Androgen Excess in 1205 Consecutively Recruited Women

Elhassan

Idkowiak

Smith

et al. 2018

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…We did not analyze the full spectrum of androgen steroids, which could influence the clinical status of our patient. According to recent reports, not only T and DHT are considered active androgens, but also 11-oxygenated-19-carbon (11oxC19) adrenal-derived steroids such as 11β-hydroxyandrostenedione (11-OHA4) and 11-ketoandrostenedione (11-KA4), 11β-hydroxytestosterone (11-OHT) and 11-ketotestosterone (11-KT), or both may play a role and should be evaluated [36][37][38][39]. In this pathway 11β-hydroxylase type 1 (CYP11B1) utilizing ANDR and T as substrates, produces 11-OHA4 and 11-OHT, respectively.…”

Section: Study Limitation-lack Of 11-oxygenated-19-carbon Androgens Ementioning

confidence: 99%

Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report

Sumińska

Bogusz‐Górna

Wegner

et al. 2020

IJMS

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Congenital adrenal hyperplasia (CAH) is the most common cause of primary adrenal insufficiency in children and adolescents. It comprises several clinical entities associated with mutations in genes, encoding enzymes involved in cortisol biosynthesis. The mutations lead to considerable (non-classic form) to almost complete (classic form) inhibition of enzymatic activity, reflected by different phenotypes and relevant biochemical alterations. Up to 95% cases of CAH are due to mutations in CYP21A2 gene and subsequent 21α-hydroxylase deficiency, characterized by impaired cortisol synthesis and adrenal androgen excess. In the past two decades an alternative (“backdoor”) pathway of androgens’ synthesis in which 5α-androstanediol, a precursor of the 5α-dihydrotestosterone, is produced from 17α-hydroxyprogesterone, with intermediate products 3α,5α-17OHP and androsterone, in the sequence and with roundabout of testosterone as an intermediate, was reported in some studies. This pathway is not always considered in the clinical assessment of patients with hyperandrogenism. The article describes the case of a 17-year-old female patient with menstrual disorders and androgenization (persistent acne, advanced hirsutism). Her serum dehydroepiandrosterone sulfate and testosterone were only slightly elevated, along with particularly high values for 5α-dihydrotestosterone. In 24 h urine collection, an increased excretion of 16α-OHDHEA—a dehydroepiandrosterone metabolite—and pregnanetriolone—a 17α-hydroxyprogesterone metabolite—were observed. The investigations that we undertook provided evidence that the girl suffered from non-classic 21α-hydroxylase deficiency with consequent enhancement of the androgen “backdoor” pathway in adrenals, peripheral tissues or both, using adrenal origin precursors. The paper presents diagnostic dilemmas and strategies to differentiate between various reasons for female hyperandrogenism, especially in childhood and adolescence.

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“…Our data demonstrate that other primates, such as Old World monkeys and apes, also synthesize these steroids. In primates, the 11-oxyandrogens are likely adrenal-derived, because their synthesis depends on the 11β-hydroxylation of A4 and T via 11β-hydroxylase, an enzyme which is almost solely expressed in the adrenal gland in these species [23,74]. Although it has been previously proposed that 11KT might be a direct product of the gonad in humans [75], the low gonadal expression of 11β-hydroxylase suggests that the contribution of gonads to the synthesis of 11-oxyandrogens is minimal.…”

Section: Discussionmentioning

confidence: 99%

Circulating 11-oxygenated androgens across species

Rege

Garber

Conley

et al. 2019

The Journal of Steroid Biochemistry and Molecular Biology

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The androgen precursors, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are produced in high amounts by the adrenal cortex primarily in humans and a few other primates. The human adrenal also secretes 11-oxygenated androgens (11-oxyandrogens), including 11βhydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11KA4), 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT), of which 11OHT and 11KT are bioactive androgens. The 11-oxyandrogens, particularly 11KT, have been recognized as biologically important testicular androgens in teleost fishes for decades, but their physiological contribution in humans has only recently been established. Beyond fish and humans, however, the presence of 11oxyandrogens in other species has not been investigated. This study provides a comprehensive analysis of a set of C 19 steroids, including the traditional androgens and 11-oxyandrogens, across 18 animal species. As previously shown, serum DHEA and DHEAS were much higher in primates than all other species. Circulating 11-oxyandrogens, especially 11KT, were observed in notable amounts in male, but not in female trout, consistent with gonadal origin in fish. The circulating concentrations of 11-oxyandrogens ranged from 0.1 to 10 nM in pigs, guinea pigs and in all the primates studied (rhesus macaque, baboon, chimpanzee and human) but not in rats or mice, and 11OHA4 was consistently the most abundant. In contrast to fish, serum 11KT concentrations were similar in male and female primates for each species, despite significantly higher circulating testosterone in males, suggesting that 11KT production in these species is not testis-dependent and primarily originates adrenal-derived 11-oxyandrogen precursors.

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Clinical significance of 11-oxygenated androgens

Cited by 62 publications

References 44 publications

Causes, Patterns, and Severity of Androgen Excess in 1205 Consecutively Recruited Women

Causes, Patterns, and Severity of Androgen Excess in 1205 Consecutively Recruited Women

Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report

Circulating 11-oxygenated androgens across species

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