isotretinoin and Teratogenesis

Isotretinoin (13-cis-retinoic acid), a derivative of vitamin A, is used in the treatment of severe acne resulting in sebum suppression induced by sebocyte apoptosis. Isotretinoin treatment is associated with several adverse effects including teratogenicity, hepatotoxicity, and dyslipidemia. Isotretinoin's effects on endocrine systems and its potential role as an endocrine disruptor are not yet adequately investigated. This review presents clinical, endocrine, and molecular evidence showing that isotretinoin treatment adversely affects the pituitary-ovarian axis and enhances the risk of granulosa cell apoptosis reducing follicular reserve. Isotretinoin is associated with pro-apoptotic signaling in sebaceous glands through upregulated expression of p53, forkhead box O transcription factors (FOXO1, FOXO3), and tumor necrosis factor-related apoptosis inducing ligand (TRAIL). Two literature searches including clinical and experimental studies respectively support the hypothesis that isotretinoin's toxicological mode of action on the pituitary-ovarian axis might be caused by over-expressed p53/FOXO1 signaling resulting in gonadotropin suppression and granulosa cell apoptosis. The reduction of follicular reserve by isotretinoin treatment should be especially considered when this drug will be administered for the treatment of acne in post-adolescent women, in whom fertility may be adversely affected. In contrast, isotretinoin treatment may exert beneficial effects in states of hyperandrogenism, especially in patients with polycystic ovary syndrome.

Topics: Acne Vulgaris; Adolescent; Apoptosis; Female; Humans; Isotretinoin; Ovary; Pituitary Gland; Polycystic Ovary Syndrome; Signal Transduction; Teratogenesis; Teratogens

This systematic review assesses effects of paternal exposure to dermatologic medications by using the former US Food and Drug Administration (FDA) pregnancy categories as a benchmark.. To assess whether systemic dermatologic medications can cause infertility and teratogenicity when taken by men.. Categories D and X dermatologic medications were identified; a systematic review of the literature and reviews of the FDA Adverse Events Reporting System and prescribing information were performed to identify the effects of these medications on male fertility and teratogenicity. A secondary search was performed to assess for other systemic dermatologic medications causing teratogenicity or infertility following paternal exposure.. A total of 13 medications met the inclusion criteria. Of 1,032 studies identified, 19 were included after a systematic review of the literature. Studies evaluating medication effects with paternal exposure were identified for 10 of the 13 evaluated medications, and evidence of a negative effect was identified for 6 medications.. We did not encounter any studies for 3 medications that met the inclusion criteria. Information submitted to the FDA Adverse Events Reporting System may not reflect the incidence of side effects.. Many former pregnancy category D and X systemic dermatologic medications also have effects on male fertility. More research and better-quality studies are required in this area, particularly studies assessing potential teratogenicity.

Topics: Acitretin; Adrenal Cortex Hormones; Colchicine; Cyclophosphamide; Dermatologic Agents; Doxycycline; Finasteride; Humans; Infertility, Male; Isotretinoin; Male; Methotrexate; Paternal Exposure; Teratogenesis; Tetracycline; Thalidomide

Isotretinoin (13-cis retinoic acid) is the most effective sebum-suppressive drug for the treatment of severe acne. Its effect depends on sebocyte apoptosis, which results from isotretinoin-induced expression of the apoptotic protein tumour necrosis factor-related apoptosis-inducing ligand, insulin-like growth factor-binding protein-3 and neutrophil gelatinase-associated lipocalin. This review proposes that the pharmacological mode of action of isotretinoin in the treatment of severe acne, acute promyelocytic leukaemia, and neuroblastoma results from apoptosis. Furthermore, apoptosis may be the underlying and unifying mechanism of the adverse effects of isotretinoin on neural crest cells (teratogenicity), hippocampal neurones (depression), epidermal keratinocytes and mucosa cells (mucocutaneous side-effects), hair follicle cells (telogen effluvium), intestinal epithelial cells (inflammatory bowel disease), skeletal muscle cells (myalgia and release of creatine kinase), and hepatocytes (release of transaminases and very low-density lipoproteins). Genetic variants of components of the apoptotic signalling cascade, such as RARA polymorphisms, might explain variations in the magnitude of isotretinoin-induced apoptotic signalling and apparently identify subgroups of patients who experience either stronger adverse effects with isotretinoin therapy or resistance to treatment.

Topics: Apoptosis; Depression; Dermatologic Agents; Hepatocytes; Humans; Isotretinoin; Neoplasms; Sebaceous Glands; Signal Transduction; Teratogenesis