Novel substrates for, and sources of, progestogens for reproduction

Steroid hormones, such as progesterone, are typically considered to be primarily secreted by the gonads (albeit adrenals can also be a source) and to exert their actions through cognate intracellular progestin receptors (PRs). Through its actions in the midbrain ventral tegmental Area (VTA), progesterone mediates appetitive (exploratory, anxiety, social approach) and consummatory (social, sexual) aspects of rodents' mating behaviour. However, progesterone and its natural metabolites ('progestogens') are produced in the midbrain VTA independent of peripheral sources and midbrain VTA of adult rodents is devoid of intracellular PRs. One approach that we have used to understand the effects of progesterone and mechanisms in the VTA for mating is to manipulate the actions of progesterone in the VTA and to examine effects on lordosis (the posture female rodents assume for mating to occur). This review focuses on the effects and mechanisms of progestogens to influence reproduction and related processes. The actions of progesterone and its 5α-reduced metabolite and neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP; allopregnanolone) in the midbrain VTA to facilitate mating are described. The findings that 3α,5α-THP biosynthesis in the midbrain occurs with mating are discussed. Evidence for the actions of 3α,5α-THP in the midbrain VTA via nontraditional steroid targets is summarised. The broader relevance of these actions of 3α,5α-THP for aspects of reproduction, beyond lordosis, is summarised. Finally, the potential role of the pregnane xenobiotic receptor in mediating 3α,5α-THP biosynthesis in the midbrain is introduced.