Abstract
Retinoic acid (RA) is the active metabolite of vitamin A but is also used as a medication, primarily for acne in which the treatment regime lasts several months. A number of studies have indicated that treatment with RA over this time period impacts the hypothalamic-pituitary-adrenal (HPA) axis and may contribute to a number of the side-effects of the drug. No studies though have investigated the short-term, early effects RA may have on the HPA axis via the transcriptional pathways activated by the RA receptor. This study investigated the action of RA over 3 days on regulatory components of the HPA axis. Several key genes involved in glucocorticoid feedback pathways in the hippocampus, hypothalamus and pituitary were unchanged after 3-days exposure to RA. Key elements though in the adrenal gland involved in corticosterone and aldosterone synthesis were altered in particular with the Cyp11b2 gene downregulated in vivo and ex vivo. The rapid, 5 h, change in Cyp11b2 expression suggested this activation may be direct. These results highlight the adrenal gland as a target of short-term action of RA and potentially a trigger component in the mechanisms by which the long-term adverse effects of RA treatment occur.
Highlights
Isotretinoin, the 13-cis isomer of retinoic acid (RA), is an effective oral treatment for severe acne first approved in the US, with FDA approval in 1982 (Layton, 2009)
This amount of Retinoic acid (RA) was chosen to be equivalent to the high dose treatment used therapeutically for acne (Cyrulnik et al, 2012) which is a mean dose of 1.6 mg/kg per day, taking into account allometric scaling for conversion between species based on body surface area (Nair and Jacob, 2016)
The dose-dependent positive induction of RA receptor beta gene (Rarb), known to be highly responsive to RA (Sucov et al, 1990), demonstrated that RA reaches the hippocampus and that the cellular machinery required for a transcriptional response is present (Figure 1A)
Summary
Isotretinoin, the 13-cis isomer of retinoic acid (RA), is an effective oral treatment for severe acne first approved in the US, with FDA approval in 1982 (Layton, 2009). Studies suggested that isotretinoin did not affect hormone levels (Palatsi et al, 1997), but subsequent investigation revealed that, to the contrary, its effects on hormone balance were broad with a complex array of effects over a typical 3-month treatment regime. Isotretinoin was reported to repress level of numerous hormones (Karadag et al, 2015), reducing adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone, prolactin, thyroid hormone and testosterone, as well as growth factors such as insulin-like growth factor-binding protein 3, insulin-like growth factor 1 (IGF-1) and growth hormone (GH). The effects were sufficiently strong for isotretinoin to be considered a potential treatment for Cushing’s syndrome (Vilar et al, 2016).
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