This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Event: 2273

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Dihydrotestosterone (DHT) levels, increased

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Explore in a Third Party Tool

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
androgen biosynthetic process	17beta-hydroxy-5alpha-androstan-3-one	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
mammals	mammals	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
During development and at adulthood	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Dihydrotestosterone (DHT) is an endogenous androgen steroid hormone. Androgens, such as DHT, induce their effects through binding to the AR in androgen-responsive tissues (Dalton & Gao, 2010; Luetjens & Weinbauer, 2012; Murashima et al., 2015; Naamneh Elzenaty et al., 2022). The level of DHT in tissue or blood is dependent on several factors, such as the synthesis, uptake/release, metabolism, and elimination from the system, which again can be dependent on biological compartment and developmental stage.

DHT is primarily synthesized from testosterone via an irreversible enzymatic reaction facilitated by 5α-reductases (Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022; Swerdloff et al., 2017). Different isoforms of this enzyme are differentially expressed in specific tissues (e.g. prostate, skin, liver, and hair follicles) at different developmental stages, and depending on disease status (Azzouni et al., 2012) ultimately affecting the local production of DHT.

An alternative (“backdoor”) pathway for DHT formation that is independent of testosterone as precursor is present in some mammals. First described in marsupials, the physiological importance of this pathway has now also been established in other mammals including humans (Renfree and Shaw, 2023). This pathway relies on the conversion of progesterone or 17-OH-progesterone to androsterone and then androstanediol through several enzymatic reactions and finally, the conversion of androstanediol into DHT probably by 17β-hydroxysteroid dehydrogenase (17β-HSD) (Miller & Auchus, 2019; Naamneh Elzenaty et al., 2022). The “backdoor” synthesis pathway is a result of an interplay between placenta, adrenal gland, and liver during fetal life (Miller & Auchus, 2019).

The conversion of testosterone to DHT by 5α-reductases in peripheral tissue is mainly responsible for the circulating levels of DHT, though some tissues express enzymes needed for further metabolism of DHT consequently leading to little release and contribution to circulating levels (Swerdloff et al., 2017).

The initial conversion of DHT into inactive steroids is primarily through 3α-hydroxysteroid dehydrogenase (3α-HSD) and 3β-HSD in liver, intestine, skin, and androgen-sensitive tissues. The subsequent conjugation is mainly mediated by uridine 5´-diphospho (UDP)-glucuronyltransferase 2 (UGT2) leading to biliary and urinary elimination from the system. Conjugation also occurs locally to control levels of highly potent androgens (Swerdloff et al., 2017).

Normal DHT levels are important for sexual development and reproduction, as well as for the function of other organs such as brain, hair, liver and skin (Azzouni et al., 2012; Dalton & Gao, 2010; Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022; Swerdloff et al., 2017).

Disruption of any of above processes may lead to increased DHT levels.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

DHT levels can be measured using immunoassays (enzyme linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), with sample preparation varying depending on the matrix of interest. Measurements can be made in serum, plasma, tissues or cell culture medium (Hsing et al., 2007; Shiraishi et al., 2008; Swerdloff et al., 2017).

Conventional immunoassays have limitations in that they can overestimate the levels of DHT compared to levels determined by gas chromatography mass spectrometry and liquid chromatography tandem mass spectrometry (Hsing et al., 2007; Shiraishi et al., 2008). This overestimation may be explained by lack of specificity of the DHT antibody used in the RIA and cross-reactivity with T in samples (Swerdloff et al., 2017).

Considerations for measurement of hormone levels have been described (Chapin & Creasy, 2012; ECHA/EFSA, 2018; Stanislaus et al., 2012).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Taxonomic applicability

DHT is present in mammals, fish, birds and amphibians (Dalton et al., 2010; Luetjens et al., 2012; Martin, 2020; Naamneh Elzenaty et al., 2022). The biologically plausible domain of taxonomic applicability is mammals, birds and amphibians since DHT is present in these groups. The empirical domain of taxonomic applicability is human, rat and mice where DHT levels have been studied. The KE description focuses on mammals, but AOP developers are encouraged to expand the applicability to other species.

Life stage applicability

DHT is synthesized from the fetal period throughout adult life (Dalton et al., 2010; Luetjens et al., 2012; Naamneh Elzenaty et al., 2022).

Sex applicability

DHT is synthesized in both males and females (Naamneh Elzenaty et al., 2022) but the role of DHT in females is less established (Swerdloff et al., 2017).

References

List of the literature that was cited for this KE description. More help

Azzouni, F., Godoy, A., Li, Y., & Mohler, J. (2012). The 5 alpha-reductase isozyme family: A review of basic biology and their role in human diseases. Adv Urol. 2012;2012:530121. https://doi.org/10.1155/2012/530121

Chapin, R. E., & Creasy, D. M. (2012). Assessment of Circulating Hormones in Regulatory Toxicity Studies II. Male Reproductive Hormones. Toxicologic Pathology, 40(7), 1063–1078. https://doi.org/10.1177/0192623312443321

Dalton, J. T., & Gao, W. (2010). Androgen Receptor. In Nuclear Receptors (pp. 143–182). Springer Netherlands. https://doi.org/10.1007/978-90-481-3303-1_6

ECHA and EFSA with the technical support of JRC, Andersson, N. et al., (2018). Guidance for the identiﬁcation of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009. EFSA Journal 2018;16(6):5311. https://doi.org/10.2903/j.efsa.2018.5311

Hsing, A. W., Stanczyk, F. Z., Bélanger, A., Schroeder, P., Chang, L., Falk, R. T., & Fears, T. R. (2007). Reproducibility of serum sex steroid assays in men by RIA and mass spectrometry. Cancer Epidemiology Biomarkers and Prevention, 16(5), 1004–1008. https://doi.org/10.1158/1055-9965.EPI-06-0792

Luetjens, C. M., & Weinbauer, G. F. (2012). Testosterone: biosynthesis, transport, metabolism and (non-genomic) actions. In Testosterone (pp. 15–32). Cambridge University Press. https://doi.org/10.1017/CBO9781139003353.003

Martin, O., Ermler, S., McPhie, J., Scholze, M., Baynes, A. (2020). Data collection in support of the Endocrine Disruption (ED) assessment for non-target vertebrates. EFSA supporting publication 2020:EN-1849. 131 pp. https://doi.org/10.2903/sp.efsa.2020.EN-1849

Murashima, A., Kishigami, S., Thomson, A., & Yamada, G. (2015). Androgens and mammalian male reproductive tract development. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1849(2), 163–170. https://doi.org/10.1016/j.bbagrm.2014.05.020

Miller, W. L., & Auchus, R. J. (2019). The “backdoor pathway” of androgen synthesis in human male sexual development. PLoS Biol. 2019 Apr 3;17(4):e3000198. https://doi.org/10.1371/journal.pbio.3000198

Naamneh Elzenaty, R., du Toit, T., & Flück, C. E. (2022). Basics of androgen synthesis and action. Best Practice & Research Clinical Endocrinology & Metabolism, 36(4), 101665. https://doi.org/10.1016/j.beem.2022.101665

Renfree, M. B., and Shaw, G. (2023). The alternate pathway of androgen metabolism and window of sensitivity. J Endocrinol. 2023 Aug 1;258(3):e220296. https://doi.org/10.1530/JOE-22-0296

Shiraishi, S., Lee, P. W. N., Leung, A., Goh, V. H. H., Swerdloff, R. S., & Wang, C. (2008). Simultaneous measurement of serum testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry. Clinical Chemistry, 54(11), 1855–1863. https://doi.org/10.1373/clinchem.2008.103846

Stanislaus, D., Andersson, H., Chapin, R., Creasy, D., Ferguson, D., Gilbert, M., Rosol, T. J., Boyce, R. W., & Wood, C. E. (2012). Society of Toxicologic Pathology Position Paper: Review Series: Assessment of Circulating Hormones in Nonclinical Toxicity Studies: General Concepts and Considerations. Toxicologic Pathology, 40(6), 943–950. https://doi.org/10.1177/0192623312444622

Swerdloff, R. S., Dudley, R. E., Page, S. T., Wang, C., & Salameh, W. A. (2017). Dihydrotestosterone: Biochemistry, physiology, and clinical implications of elevated blood levels. Endocr Rev. 2017 Jun 1;38(3):220-254. https://doi.org/10.1210/er.2016-1067