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On the other hand, a post-marketing surveillance study reported 13 pregnancies where the father was under treatment with acitretin. Among all 13 babies, only one had malformations which could not be associated with retinoid embryopathy. There were communicated six spontaneous abortions and the rest were reported as healthy neonates. The study was limited but the authors concluded that males under treatment of retinoids can plan fatherhood (41).

Scientists have conducted studies showing the severe teratogenic effects since isotretinoin was introduced on the market, both in laboratory animals and humans (36). In humans, malformations induced by isotretinoin includes cranio-facial malformations, cardiac, thymic and central nervous abnormalities, but the commonest are microtia, anotia, micrognathia, aortic arch or heart defects, thymic ectopia or aplasia or cerebellar vermis agenesis (42-44).

Thse malformations can be explained by the massive cell death that occurs in vertebrates during neural development and due to the fact that apoptosis is a contributor to nervous system development that requires a proper apoptotic signaling during embryogenesis (45,46).

ATRA is responsible for inducing reprogramming of cranial neural crest gene expression with increased apoptosis secondly (47,48). Studies conducted on animals have confirmed that isotretinoin administration during pregnancy can increase the apoptosis of neural crest cells and the appearance of malformations (49-52). Malformations are caused by excessive cell death limited to trigeminal ganglion neuroblasts during ganglion formation.

These are proposed by studies on mice which concluded that increased cell apoptosis is the principal mechanism involved in cranio-facial malformations induced by isotretinoin administration (53).

Another teratogenic effect of this drug is represented by heart defects and aortic arch malformations. These abnormalities can be explained by impaired migrations of neural crest cells.

It is well known that morphogenesis and the development of cardiovascular tissue depend on coordinated regulation of cell proliferation and apoptosis (54). ATRA action on cardiovascular tissue is specific during early development, such as anteroposterior patterning of the heart or endocardial cushion formation (55-58). All of these data outline that neural crest cell apoptosis plays an essential role in the teratogenicity induced by isotretinoin treatment. According to the US-FDA, isotretinoin is the first line of treatment for severe acne vulgaris causing a reduction in sebum production, acne lesions and acne scarring.

It has limited indications in the case of non-nodular, inflammatory acne, where the administration of isotretinoin is recommended to patients with psychological distress caused by prolonged acne lesions (38). It also has shown efficiency in reducing anxiety and depression caused by the aesthetic aspect of the skin affected by acne vulgaris.

This treatment has demonstrated effectiveness to clear most superficial or deep inflammatory nodules. There is sufficient data to support the major action of isotretinoin is human sebocyte apoptosis. In addition, other cells such as neural crest cells or neural crest-derived neuroblastoma cells are very susceptible to isotretinoin-induced apoptosis. This mechanism is the base for numerous side effects induced by isotretinoin of which the most cited and significant is teratogenicity.

There are numerous studies that have aimed to analyze the teratogenic effect induced by isotretinoin treatment in women during embryogenesis, showing the possible congenital malformations that may occur.

In recent years, research has focused on the study of the possible side effects of isotretinoin in fertile men, without clear data to date. CCD analyzed and wrote the mechanism of action of isotretinoin. RCP analyzed the data from the literature regarding the teratogenic effect of isotretinoin on fertile males and contributed to the writing of the manuscript. AP analyzed the teratogenic effect on fertile women and was responsible for the writing of the relevant section. RGM analyzed the apoptosis effect of isotretinoin in inducing teratogenicity and wrote the relevant section of the manuscript.

MCD is the corresponding author and was also involved in the conception and design of the review, and contributed in the writing of the manuscript. All authors critically revised the manuscript and approved the final version of the manuscript to be published.

The iPLEDGE test case. Indian Dermatol Online J. Implications for PTEN mutation in prostate cancer. Accessed May 28, 2020. Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy. J Skin Sex Transm Dis. Am J Biomed Sci. Pediatr Pathol Lab Med. Birth Defects Res C Embryo Today.

J Craniofac Genet Dev Biol. In: Retinoids in Normal Development and Teratogenesis. Oxford University Press, New York, pp281-295, 1991. Crit Rev Oral Biol Med.

To find out more, you may read our Privacy Policy. The recommended dose is 0. 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.

Introduction Isotretinoin or 13-cis-retinoic acid is an oral derivate of vitamin A that is used in the treatment of numerous dermatologic diseases such as ichthyosis, hidradenitis suppurativa, rosacea, scarring alopecia, non-melanoma skin cancer prophylaxis, but mainly used in sebaceous gland pathology (1).