Isotretinoin administration improves sperm production in men with infertility from oligoasthenozoospermia: a pilot study

Abstract

There is currently no effective medical therapy for men with infertility due to oligoasthenozoospermia (OA). As men with abnormal sperm production have lower concentrations of 13-cis-retinoic acid in their testes, we hypothesized that men with infertility from OA might have improved sperm counts when treated with isotretinoin (13-cis-retinoic acid).We conducted a single-site, single-arm, pilot study to determine the effect of therapy with isotretinoin on sperm indices in 19 infertile men with OA. Subjects were men between 21 and 60 years of age with infertility for longer than 12 months associated with sperm concentrations below 15 million sperm/ml. All men received isotretinoin 20 mg by mouth twice daily for 20 weeks. Subjects had semen analyses, physical examinations and lab tests every four weeks during treatment. Nineteen men enrolled in the study. Median (25th, 75th) sperm concentration increased from 2.5 (0.1, 5.9) million/ml at baseline to 3.8 (2.1, 13.0) million/ml at the end of treatment (p=0.006). No significant changes in sperm motility were observed. There was a trend towards improved sperm morphology (p=0.056). Six pregnancies (three spontaneous and three from ICSI) and five births occurred during the study. Four of the births, including all three of the spontaneous pregnancies, were observed in men with improvements in sperm counts with isotretinoin therapy. Treatment was well tolerated. Isotretinoin therapy improves sperm production in some men with OA. Additional studies of isotretinoin in men with infertility from OA are warranted.

Does In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug‐Drug Interactions? Preclinical and Clinical Studies With 13‐cis‐Retinoic Acid

“…The mean (%CV) steady-state concentration (C avg,ss ) values for 13cisRA, atRA, and 4-oxo-13cisRA in the study subjects were 0.88 μM (46%), 0.069 μM (22%), and 4.2 μM (59%), respectively (Figure 4). These concentrations were in close agreement with the concentrations measured in previous studies 17 and used in the DDI predictions. No increase in dextromethorphan or dextrorphan area under the concentration-time curve from zero to infinity (AUC 0-∞ ) was observed after retinoid treatment in comparison with control ( Figure 4 and Table 2).…”

“…The change in CYP2D6 expression in vivo following 13cisRA dosing was predicted based on the magnitude of CYP2D6 mRNA downregulation in human hepatocytes and average unbound concentrations (f u,plasma × average plasma concentration (C avg )) of 13cisRA, atRA, and 4-oxo-13cisRA. For predictions, the average steady-state plasma concentrations measured previously by us 17 were used. The overall effect of the three compounds on CYP expression in vivo was predicted assuming that all three precipitants (13cisRA, atRA, and 4-oxo-13cisRA) bind to the same receptor to result in altered CYP expression via a competitive mechanism, as described previously.…”

“…All the retinoids were extensively bound in the media and in plasma ( Table 1). Using reported average plasma concentrations of 13cisRA, atRA, and 4-oxo-13cisRA after treatment with 13cisRA, 17 the decrease in CYP2D6 expression following 13cisRA treatment was predicted based on each retinoid exposure alone and in combination ( Table 1). An up to 77% decrease in CYP2D6 expression was predicted after 13cisRA dosing.…”

Low dose of isotretinoin: A comprehensive review

“…The authors concluded that isotretinoin therapy has positive effect in improvement of sperm production in some men with oligoasthenozoospermia (Amory et al, 2017).…”

“…Four of the births, including all three of the spontaneous pregnancies, were observed in men oligoasthenozoospermia who showed improvements in their seminal parameters, mostly sperm counts, with isotretinoin therapy. The authors concluded that isotretinoin therapy has positive effect in improvement of sperm production in some men with oligoasthenozoospermia (Amory et al, ).…”