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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
Androgen receptor, Agonism Testosterone synthesis by ovarian theca cells, Reduction

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Androgen receptor agonism leading to reproductive dysfunction Indirectly Leads to Strong Weak

Taxonomic Applicability

Name Scientific Name Evidence Links

How Does This Key Event Relationship Work

Weight of Evidence

Biological Plausibility

Negative feedback of circulating androgens (e.g., testosterone) on GnRH release from the hypothalamus and/or gonadotropin release from the pituitary is a well established physiological phenomenon in vertebrate endocrinology (Norris 2007). While similar processes of negative feedback of sex steroids on gonadotropin expression and release have been established in fish (Levavi-Sivan et al. 2010), there are many remaining uncertainties about the exact mechanisms through which feedback takes place in fish as well as other vertebrates. For example, feedback is thought to involve a complex interplay of neurotransmitter signaling, kisspeptins, and the follistatin/inhibin/activin system (Trudeau et al. 2000; Trudeau 1997; Oakley et al. 2009; Cheng et al. 2007). In addition, the nature of the feedback produced by androgens is dependent on the concentration, form of the androgen (e.g., aromatizable versus non-aromatizable), life-stage and likely species (Habibi and Huggard 1998; Trudeau et al. 2000; Gopurappilly et al. 2013). Therefore, while the concept that xenobiotics which act as AR agonists could elicit a negative feedback response in vivo is plausible, there is sufficient complexity and uncertainty in the mechanisms to believe that reliable prediction of this key event may be challenging.

Empirical Support for Linkage

There is a relatively strong body of evidence demonstrating that gonadectomy and/or treatment with potent AR antagonists can increase circulating concentrations of gonadotropins in fish and that those effects can be reversed by treatment with testosterone (reviewed in (Habibi and Huggard 1998; Levavi-Sivan et al. 2010)). However, we are currently unaware of any studies conducted with xenobiotic or pharmaceutical androgen agonists that measured effects on circulating gonadotropins.

Uncertainties or Inconsistencies

See biological plausibility section above regarding current uncertainties in the mechanisms through which AR agonists may reduce gonadotropin secretion.

Quantitative Understanding of the Linkage

Given the uncertainties in the specific mechanism(s) of negative feedback that are involved and the lack of data on circulating gonadotropin concentrations following exposure to exogenous androgen agonists there is currently no quantitative understanding that would translate relative binding affinity and/or effect concentrations in an AR-mediated transcriptional activation assay into expected impacts on circulating gonadotropin concentrations.

Evidence Supporting Taxonomic Applicability


  • Norris DO. 2007. Vertebrate Endocrinology. Fourth ed. New York: Academic Press.
  • Levavi-Sivan B, Bogerd J, Mananos EL, Gomez A, Lareyre JJ. 2010. Perspectives on fish gonadotropins and their receptors. General and comparative endocrinology 165(3): 412-437.
  • Trudeau VL, Spanswick D, Fraser EJ, Lariviére K, Crump D, Chiu S, et al. 2000. The role of amino acid neurotransmitters in the regulation of pituitary gonadotropin release in fish. Biochemistry and Cell Biology 78: 241-259.
  • Trudeau VL. 1997. Neuroendocrine regulation of gonadotropin II release and gonadal growth in the goldfish, Carassius auratus. Reviews of Reproduction 2: 55-68.
  • Oakley AE, Clifton DK, Steiner RA. 2009. Kisspeptin signaling in the brain. Endocrine reviews 30(6): 713-743.
  • Cheng GF, Yuen CW, Ge W. 2007. Evidence for the existence of a local activin follistatin negative feedback loop in the goldfish pituitary and its regulation by activin and gonadal steroids. The Journal of endocrinology 195(3): 373-384.
  • Habibi HR, Huggard DL. 1998. Testosterone regulation of gonadotropin production in goldfish. Comparative biochemistry and physiology Part C, Pharmacology, toxicology & endocrinology 119(3): 339-344.
  • Gopurappilly R, Ogawa S, Parhar IS. 2013. Functional significance of GnRH and kisspeptin, and their cognate receptors in teleost reproduction. Frontiers in endocrinology 4: 24.