The brain as a target for steroid hormone action

IT is now well established that progesterone can either facilitate or inhibit the effects of oestrogen on gonadotrophin release and behaviour1. Whether facilitation or inhibition is observed depends primarily on the time interval between exposure to oestrogen and progesterone, but the mechanism by which progesterone exerts these effects remains unknown. Attempts to demonstrate progesterone receptor sites within the brain and pituitary have given equivocal results2–10, leading to speculation that the central effects of progesterone may be mediated through a mechanism fundamentally different from that found in peripheral tissues1,2,6. More recently, however, several studies have suggested that oestrogen-inducible progestin receptor systems similar to those found in peripheral progesterone target tissues can be identified in the brain and pituitary if sufficiently sensitive and specific experimental procedures are used11–14. We summarise here work from our laboratory which indicates that, in the rat brain, there are in fact two anatomically distinct progestin receptor systems, one of which differs strikingly from the systems identified previously in neural and non-neural tissues in that it is apparently insensitive to oestrogen.

Oestrogen modulates progestin receptor concentrations in some rat brain regions but not in others

Putative progestin receptors have been characterized in brain and pituitary tissue from untreated and estrogenprimed ovariectomized-adrenalectomized rats. The properties of these sites appear indistinguishable from those of cytoplasmic progestin receptors from the uterus: 1) sedimentation coefficient of 7S, which is reduced by half in the presence of 0.3 m KC1; 2) specificity of binding which strongly favors synthetic and natural progestins as opposed to glucocorticoids, androgens, and estrogens; 3) a dissociation constant for binding the synthetic progestin [3H]R5020 (17α,21-dimethyl-19-norpregna-4, 9-diene-3,20- dione) of 0.3 nm; and 4) similar rates of formation and dissociation of the [3H]R5020-receptor complexes. In these respects, the estrogen-inducible and noninducible receptors of the brain also appear to be indistinguishable from each other. Estrogen induction of progestin receptors is apparent in uterus (6-fold), pituitary (8-fold), mediobasal hypothalamus (4-fold), and preoptic area (4-fold), a...

Progestin receptors in rat brain: distribution and properties of cytoplasmic progestin-binding sites.

Estrogen and progesterone modulate gene expression in rodents by activation of intracellular receptors in the hypothalamus, which regulate neuronal networks that control female sexual behavior. However, the neurotransmitter dopamine has been shown to activate certain steroid receptors in a ligand-independent manner. A dopamine receptor stimulant and a D1 receptor agonist, but not a D2 receptor agonist, mimicked the effects of progesterone in facilitating sexual behavior in female rats. The facilitory effect of the neurotransmitter was blocked by progesterone receptor antagonists, a D1 receptor antagonist, or antisense oligonucleotides to the progesterone receptor. The results suggest that in rodents neurotransmitters may regulate in vivo gene expression and behavior by means of cross-talk with steroid receptors in the brain.

https://science.sciencemag.org/content/sci/265/5176/1246.full.pdf

Convergent pathways for steroid hormone- and neurotransmitter-induced rat sexual behavior

Estrogens and progestins alter electrical and chemical features of nerve cells, particularly in hypothalamus. Temporally, these events follow nuclear receptor occupation by these steroids, although not all effects have been proved to depend on translocation of receptors to the nucleus. Narrowing studies to focus on particular medial hypothalamic cells has been useful for understanding some of the actions of these steroids in brain. The variety of morphological, chemical, and electrical effects allow for a multiplicity in the cellular functions controlled by these hormones.

https://science.sciencemag.org/content/sci/219/4586/808.full.pdf

Actions of estrogens and progestins on nerve cells

When the action of a hormone on a tissue is studied, the biochemical condition of the tissue or substrate prior to administration of the hormone should always be considered. Diverse factors, such as genetic sex, nutritional state, temperature, time of day, and season of year, may influence the substrate. Only when these and other factors are controlled for can one be sure that experimental samples begin from a relatively homogeneous baseline, and only in this way can one accurately assess the effects of a hormone on this baseline. Extraordinary emphasis on this stricture is required for progesterone and its actions on neural and genital tissues. This is so because the effects of progesterone are very much dependent on the previous, concurrent, and subsequent influences of estrogenic hormones on target tissue substrates. These temporal factors determine whether progesterone will facilitate or inhibit estrogen-dependent processes. In this paper, we will first describe, at a molar level, the interaction of progesterone with estrogen-sensitive neural tissues that regulate the expression of female sexual behavior and the release of gonadotropic hormones. Later, we will discuss, at a biochemical level, possible mechanisms by which progesterone can exert both facilitatory and inhibitory influences on sexual behavior and gonadotropin release. This section will include data on estrogen and progesterone uptake and on possible mediation of progesterone effects by neurotransmitters. Also included in this discussion will be a comparison between the inhibitory actions of progesterone and those of synthetic antiestrogens on estrogen-dependent neural processes. To conclude, we will suggest that progesterone-sensitive neural systems operate with a precision that is attributable more to interneuronal channeling of information to or from estrogen-sensitive areas than to intranuclear programming of biochemical events.

H. H. Feder

Papers

Progesterone: its role in the central nervous system as a facilitator and inhibitor of sexual behavior and gonadotropin release.