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Event: 2298

Key Event Title

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

Decrease, intratesticular testosterone levels

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

Decrease, intratesticular testosterone

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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
Organ

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

Organ term
testis

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
testosterone biosynthetic process	testosterone	decreased

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

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Decreased testosterone synthesis leading to short AGD	KeyEvent	Terje Svingen (send email)	Under development: Not open for comment. Do not cite	Under Development
Decreased testosterone synthesis leading to hypospadias	KeyEvent	Terje Svingen (send email)	Under development: Not open for comment. Do not cite
Decreased testosterone synthesis leading to nipple retention	KeyEvent	Terje Svingen (send email)	Under development: Not open for comment. Do not cite

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
Vertebrates	Vertebrates	Moderate	NCBI
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
Male	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

This KE refers to decreased testosterone biosynthesis in the testis (male); i.e. intratesticular testosterone levels. It is therefore considered distinct from KEs describing circulating testosterone levels, or levels in any other tissue or organ of vertebrate animals. It is also distinct from indirect cell-based assays measuring effects on testosterone synthesis, including in vitro Leydig cells.

In males, the testis is the primary site of testosterone biosynthesis via the steroidogenesis pathway – an enzymatic pathway converting cholesterol into all the downstream steroid hormones (Miller and Auchus 2010). In mammals, the Leydig cells are considered the primary site of steroidogenesis in the testis. Although generally correct, there is evidence to suggest the involvement of Sertoli cells during fetal stages in e.g. mouse and human testis, but with Leydig cells being sufficient in adult life (O’Donnell et al 2022).

Testicular testosterone synthesis is primarily regulated by the hypothalamic-pituitary-gonadal (HPG) axis, with Gonadotropin-releasing hormone (GnRH) from the hypothalamus controlling the secretion of Luteinizing hormone (LH) from the pituitary that ultimately binds to the LH receptors on Leydig cells to stimulate steroidogenesis. Notably, the timing of HPG axis activation during development varies between species. In humans, human chorionic gonadotropin (hCG) act similarly to LH and appear to be critical in stimulating testosterone synthesis in the fetal testis (Huhtaniemi 2025), whereas in the mouse testosterone synthesis in the fetal testis appears to be independent of pituitary gonadotropins even though LH is detectable during late gestation O’Shaughnessy et al 1998). Irrespective of testosterone being stimulated by gonadotropins or occurring de novo, however, it is essential for masculinization of the developing fetus, initiation of puberty, and maintain reproductive, and other, functions in adulthood.

Notably, intratesticular testosterone concentration is significantly higher than serum testosterone levels, typically ranging from 30- to 200-fold greater in mammals, including humans (Turner et al 1984; McLachlan et al 2002; Coviello et al 2004).

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

Testosterone levels can be quantified in testis tissue (ex vivo, in vivo). Methods include traditional immunoassays such as ELISA and RIA, advanced techniques like LC-MS/MS, and liquid scintillation spectrometry following radiolabeling (Shiraishi et al., 2008).

Domain of Applicability

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

This key event (KE) is applicable to all male vertebrates with testis that produce testosterone.

References

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

Coviello, A.D., Bremner, W.J., Matsumoto, A.M., Herbst, K.L., Amory, J.K., Anawalt, B.D., Yan, X., Brown, T.R., Wright, W.W., Zirkin, B.R. and Jarow, J.P. (2004). Intratesticular Testosterone Concentrations Comparable With Serum Levels Are Not Sufficient to Maintain Normal Sperm Production in Men Receiving a Hormonal Contraceptive Regimen. J Androl, 25:931-938. https://doi.org/10.1002/j.1939-4640.2004.tb03164.x

Huhtaniemi, I.T. (2025). Luteinizing hormone receptor knockout mouse: What has it taught us? Andrology, In Press. https://doi.org/10.1111/andr.70000

McLachlan, R.I., O’Donnell, L., Stanton, P.G., Balourdos, G., Frydenberg, M., de Kretser, D.M. and Robertson, D.M. (2002). Effects of testosterone plus medroxyprogesterone acetate on semen quality, reproductive hormones, and germ cell populations in normal young men. J Clin Endocriol Metab, 87:546-556. https://doi.org/10.1210/jcem.87.2.8231

Miller, W.L. and Auchus, R.J. (2010). The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders. Endocr Rev, 32(1):81-151. https://doi.org/10.1210/er.2010-0013

O’Donnell, L., Whiley, P.A.F., and Loveland, K.L. (2022). Activin A and Sertoli Cells: Key to Fetal Testis Steroidogenesis. Front Endocrinol, 13:898876. https://doi.org/10.3389/fendo.2022.898876

O’Shaughnessy, P.J., Baker, P., Sohnius, U., Haavisto, A.M., Charlton, H.M. and Huhtaniemi, I. (1998). Fetal development of Leydig cell activity in the mouse is independent of pituitary gonadotroph function. Endocrinology, 139:1141-1146. https://doi.org/10.1210/endo.139.3.5788

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

Turner, T.T., Jones, C.E., Howards, S.S., Ewing, L.L., Zegeye, B. and Gunsalus, G.L. (1984). On the androgen microenvironment of maturing spermatozoa. Endocrinology, 115:1925-1932. https://doi.org/10.1210/endo-115-5-1925