The combination of sufficient AR and PR activation can suppress circulating testosterone levels into the castrate range in men (i.e., complete suppression of gonadal testosterone production and circulating testosterone levels decreased by about 95%). As such, combined progestogenic activity may serve to further increase the myotrophic–androgenic ratio for a given AAS. GABAA receptor modulation
Some AAS, such as testosterone, DHT, stanozolol, and methyltestosterone, have been found to modulate the GABAA receptor similarly to endogenous neurosteroids like allopregnanolone, 3α-androstanediol, dehydroepiandrosterone sulfate, and pregnenolone sulfate. It has been suggested that this may contribute as an alternative or additional mechanism to the neurological and behavioral effects of AAS. Comparison of AAS
AAS differ in a variety of ways including in their capacities to be metabolized by steroidogenic enzymes such as 5α-reductase, 3-hydroxysteroid dehydrogenases, and aromatase, in whether their potency as AR agonists is potentiated or diminished by 5α-reduction, in their ratios of anabolic/myotrophic to androgenic effect, in their estrogenic, progestogenic, and neurosteroid activities, in their oral activity, and in their capacity to produce hepatotoxicity. 5α-Reductase and androgenicity
Testosterone can be robustly converted by 5α-reductase into DHT in so-called androgenic tissues such as skin, scalp, prostate, and seminal vesicles, but not in muscle or bone, where 5α-reductase either is not expressed or is only minimally expressed. As DHT is 3- to 10-fold more potent as an agonist of the AR than is testosterone, the AR agonist activity of testosterone is thus markedly and selectively potentiated in such tissues.
FASPS is the first disorder to link known core clock genes directly with human circadian sleep disorders. As the PER2 mutation is not exclusively responsible for causing FASPS, current research has continued to evaluate cases in order to identify new mutations that contribute to the disorder. Mechanisms (Per2 and CK1)
Two years after reporting the finding of FASPS, Ptáčeks and Fus groups published results of genetic sequencing analysis on a family with FASPS. They genetically mapped the FASPS locus to chromosome 2q where very little human genome sequencing was then available. Thus, they identified and sequenced all the genes in the critical interval. One of these was Period2 (Per2) which is a mammalian gene sufficient for the maintenance of circadian rhythms. Sequencing of the hPer2 gene (h denoting a human strain, as opposed to Drosophila or mouse strains) revealed a serine-to-glycine point mutation in the Casein Kinase I (CK1) binding domain of the hPER2 protein that resulted in hypophosphorylation of hPER2 in vitro. The hypophosphorylation of hPER2 disrupts the transcription-translation (negative) feedback loop (TTFL) required for regulating the stable production of hPER2 protein. In a wildtype individual, Per2 mRNA is transcribed and translated to form a PER2 protein. Large concentrations of PER2 protein inhibits further transcription of Per2 mRNA. CK1 regulates PER2 levels by binding to a CK1 binding site on the protein, allowing for phosphorylation which marks the protein for degradation, reducing protein levels. Once proteins become phosphorylated, PER2 levels decrease again, and Per2 mRNA transcription can resume.