Nortestosterone-derived synthetic progestogens do not activate the progestogen receptor of Murray–Darling rainbowfish (Melanotaenia fluviatilis) but are potent agonists of androgen receptors alpha and beta

Synthetic progestogens derived from 19-nortestosterone can elicit a number of adverse effects in fish including decreased fecundity, altered hormone levels, disruption of normal breeding cycles, expression in females of male-specific biomarkers, development of male secondary sexual characteristics in females, and changes in the expression of steroidogenic genes. A recent in vitro study showed that a number of representatives from this class of progestins were potent agonists of fathead minnow androgen receptor (AR) and only weak agonists of progesterone receptor (PR) from the same species. This confirms that synthetic progestogens derived from 19-nortestosterone function as AR agonists in otomorphs, which express a single AR subtype. However, numerous percomorphes are known to express two AR subtypes. We have recently shown that ARα and ARβ from Murray–Darling rainbowfish (Melanotaenia fluviatilis) respond differently to certain androgens and anti-androgens. The goal of the present study was to determine concentration–response profiles for selected progestins in transactivation assays driven by rainbowfish ARα, ARβ and PR in order to ascertain the relative potency of progestins against these receptors. As a means of confirming the expected activity of the progestins and reference compounds used in the study against human-derived receptors, we also established concentration–response relationships using transactivation assays driven by human PR and AR. We found that all five 19-nortestosterone-derived progestins tested were highly potent agonists of rainbowfish ARα, but that only four of the five progestins were potent agonists of rainbowfish ARβ, with norgestimate exhibiting only weak activity against rainbowfish ARβ. The spironolactone-derived progestin, drospirenone, was not an agonist of rainbowfish ARα or ARβ but was a weak agonist of rainbowfish PR. None of the 19-nortestosterone-progestins activated rainbowfish PR. These findings confirm that the majority of 19-nortestosterone-derived progestins are likely to elicit strong androgenic activity in teleosts, but that PR-mediated effects would be minimal. In species that express two AR subtypes similar to rainbowfish ARα and ARβ, biological processes mediated by a specific subtype may be affected differently by progestins such as norgestimate.