Teratogenic effect of isotretinoin in both fertile females and males (Review)

Abstract

Isotretinoin is an oral derivate of vitamin A that has been used since 1982 for the treatment of multiple dermatologic conditions such as severe acne, rosacea, scarring alopecia, ichthyosis or non-melanoma skin cancer prophylaxis. The recommended dose is 0.5-1 mg/kg/day for a period of 4-6 months in sebaceous gland pathologies. There are many adverse effects caused by isotretinoin but by far the most important is the teratogenicity induced by this drug which is estimated to have a 20-35% risk to infants that are exposed to isotretinoin in utero and includes numerous congenital defects such as craniofacial defects, cardiovascular and neurological malformations or thymic disorders. Isotretinoin induces apoptosis and cell cycle arrest in human sebocytes, emphasizing these as processes associated with its teratogenic effect. The aim of this review is to analyze the latest literature data regarding the teratogenic effect of isotretinoin for both fertile females and males and its biological effects underlying the occurrence of congenital malformations under the influence of isotretinoin.

In vivo cytogenotoxicity testing of isotretinoin by the micronucleus assay in the blood of male Sprague-Dawley rats Isotretinoin is cytotoxic and genotoxic

“…The drastic change in erythropoiesis in bone marrow induced by ISO treatment would affect fluctuations of %PCE or % MNPCE per non-micronucleated erythrocytes in the MN test. It is known that the ISO achieves remarkable pharmacological efficacy in the treatment of severe acne, by influencing the basic cellular processes such as division, growth, survival, differentiation, and apoptosis (Tsukada et al, 2000;Rigopoulos et al, 2010;Miura, 2011;Nelson et al, 2011;Layton, 2014;Melnik, 2017;Draghici et al, 2021). Finally, it is worth mentioning that ISO and its analog structures tretinoin, and 4-oxo-isotretinoin are the major systemic metabolites identified in systemic circulation following oral administration of ISO (Colburn et al, 1983), and its plasma concentration is about 4-fold higher than that of the parent drug after multiple dosing (Sadeghzadeh-Bazargan et al, 2021).…”

“…The exact mechanism of the therapeutic action of ISO remains unknown. However, several studies have shown that this drug induces apoptosis in sebaceous gland cells (Melnik, 2017;Reigada et al, 2017;Draghici et al, 2021). The use of retinoids in cancer therapy is restricted because of their severe cytotoxic reactions, particularly if administered systemically in aqueous solutions (Diniz et al, 2008).…”

“…Concerns related to ISO use arise from the selection of the most optimal dosage regimen with the best efficacy and lesser side effect. Many adverse effects have been described for isotretinoin, but by far the most serious and frightening side effect of this drug, at all therapeutic doses, is the induction of congenital birth defects (Gad and Fain, 2014;Al-Othman et al, 2019;Draghici et al, 2021). A review of the National Collections data (Medsafe, 2018) indicated that despite the well-known teratogenic effects of ISO, pregnancy exposures still occur.…”

Isotretinoin Treatment for Autosomal Recessive Congenital Ichthyosis in a Golden Retriever

“…Retinoids are structurally and functionally related to vitamin A [ 14 ] with proven functions in the skin based on the modulation of epidermal maturation, as well as keratinocyte differentiation, apoptosis, immune function and carcinogenesis [ 15 , 16 ]. Moreover, isotretinoin was found to induce apoptosis and cell cycle arrest in human sebocytes [ 17 ]. As a result, retinoids decrease thickening and scaling of the skin, decrease erythema [ 14 , 18 ] and facilitate wound healing [ 19 ].…”

The Effects of Isotretinoin on The Menstrual Cycle: A Cross-Sectional Study

“…This points to the influence of this drug on hormonal changes in females. Evidence shows that isotretinoin, due to its derivation from vitamin A, is highly teratogenic and is therefore strictly contraindicated in women of reproductive age unless effective contraception is taken, often in the form of oral contraceptive pills [ 24 , 25 ]. A study done by Peck et al reported that in patients treated with isotretinoin, no changes in hormone levels were seen, suggesting a different cause for menstruation irregularities [ 26 ].…”