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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
Androgen receptor, Agonism Gonadotropins, circulating concentrations, Reduction

AOPs Referencing Relationship

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

Taxonomic Applicability

Name Scientific Name Evidence Links

How Does This Key Event Relationship Work

Weight of Evidence

Biological Plausibility

Circulating concentrations of steroid hormones are tightly regulated via positive and negative feedback loops that operate through endocrine, autocrine, and/or paracrine mechanisms within the hypothalamic-pituitary-gonadal axis (Norris 2007). Gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) secretion from the pituitary is a key regulator of gonadal steroid biosynthesis. Negative feedback of androgens or estrogens at the level of the hypothalamus and/or pituitary can reduce gonadotropin secretion by pituitary gonadotropes either indirectly due to decreased GnRH signaling from the hypothalamus or directly through intrapituitary regulators of gonadotropin expression (e.g., activin, follistatin, inhibin) (Norris 2007; Habibi and Huggard 1998).

  • The specific mechanisms through which negative feedback of AR agonists on the hypothalamus and pituitary are mediated in fish are not fully understood. However, it is thought that GABAergic and dopaminergic neurons may be important mediators of sex steroid feedback on gonadotropin releasing hormone (GnRH) release from the hypothalamus (Trudeau et al. 2000; Trudeau 1997). Recent evidence also suggests an important role of kisspeptin neurons, which have been shown to express both AR and ERα are important mediators of feedback response to circulating androgen concentrations (Oakley et al. 2009). Follistatin expression in the pituitary has also been cited as a key regulator of gonadotropin expression that is directly regulated by androgens and estrogens (Cheng et al. 2007). Regardless of the exact mechanisms, negative feedback of androgens on GnRH and/or gonadotropin release from the hypothalamus and/or pituitary is a well established endocrine phenomenon.

Empirical Support for Linkage

Include consideration of temporal concordance here

Uncertainties or Inconsistencies

Due to uncertainties regarding the exact mechanisms through which exogenous androgens mediate a negative feedback response this initiation of a negative feedback response is not directly observable. Negative feedback would generally be inferred through a decrease in gonadotropin release and associated declines in circulating gonadotropin concentrations.

Quantitative Understanding of the Linkage

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Evidence Supporting Taxonomic Applicability


• Norris DO. 2007. Vertebrate Endocrinology. Fourth ed. New York: Academic Press.

• 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.

• 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.