Long-term effect of systemic isotretinoin on female fertility

Background/objective: Acne vulgaris is one of the most common diseases of the youth. Systemic isotretinoin is the only drug which acts on all of the etiopathogenic mechanisms of acne. Isotretinoin has some well-known side effects. Besides these, there is a suspicion whether it affects fertility or not. Previously, we conducted a study about isotretinoin’s effect on ovarian reserve which showed deteriorative reserve. In this study, we aimed to evaluate the long-term effects of systemic isotretinoin on female fertility.

Materials and methods: Of the 82 female patients who were enrolled in the first study, 79 patients were included in this study. Twelve months after the end of systemic isotretinoin treatment, patients were reevaluated by using the same parameters which include anti-Mullerian hormone (AMH), ovarian volume (OV), antral follicle count (AFC), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, free testosterone and total testosterone.

Results: The changes in the mean AMH, OV and AFC were statistically significant between the sixth and eighteenth months (the end of systemic isotretinoin treatment and 12 months treatment free). The mean AMH, OV and AFC values at the beginning and at the 18th month were statistically similar.

Conclusion: The deteriorative effects of systemic isotretinoin treatment on ovarian reserve, which can be accepted as an indicator of female fertility, diminish in time.     

异维A酸治疗寻常痤疮疗效观察

寻常痤疮４４例，随机双盲分为Ａ和Ｂ２组。Ａ组１９例：男性１１例，女性８例，年龄２２±ｓ４ａ，服精制豆油胶丸，１０ｍｇ／丸，２－３丸／ｄ×１２ｗｋ。Ｂ组２５例；男性２０例，女性５例，年龄２４±４ａ，服异维Ａ酸胶丸，１０ｍｇ／丸，２－３丸／ｄ×１２ｗｋ。结果：总有效率Ａ组为５％，Ｂ组为９２％，经Ｒｉｄｉｔ分析ｐ＜０．０５。异维Ａ酸主要不良反应为口干。     

The effect of oral isotretinoin on visual contrast sensitivity and amount of lacrimation in patients with acne vulgaris

Context: Acne vulgaris is a puberty-onset chronic inflammatory disease of the pilosebaceous unit. Isotretinoin is a derivative of vitamin A commonly used for severe and nodulocystic acne. While isotretinoin has many side effects related to the eye, visual system and lacrimation, there is no information regarding isotretinoin’s influence on contrast sensitivity.

Aim: To investigate the effect of isotretinoin on visual contrast sensitivity and the amount of lacrimation.

Materials and methods: The study included 25 patients (16 females and 9 males) who underwent isotretinoin treatment. The treatment duration ranged from 4 to 7 months. Patients were examined both before the start and at the end of treatment using the Schirmer test in each eye. The contrast sensitivity measurement was performed both individually for each eye and in a binocular fashion using the Pelli–Robson Sensitivity Chart.

Results: The results of the Schirmer test before treatment were 19.74?±?3.63?mm for the right eye and 19.66?±?3.63?mm for the left eye. Post-treatment measurement results were 17.24?±?3.5?mm for the right eye and 16.68?±?3.73?mm for the left eye. There was a statistically significant difference between the before and after treatment measurements (p?<?0.000). Before treatment, contrast sensitivity was 1.45?±?0.19 for the right eye and 1.42?±?0.2 for the left eye. The binocular measurement was 1.54?±?0.14. After treatment, the right eye was 1.47?±?0.19, the left eye was 1.46?±?0.18, and the binocular measurement was 1.54?±?0.18. There were no statistically significant differences between before and after treatment (p?>?0.05).

Discussion: There are contradicting reports on the results of the Schirmer test. The only similar study that has evaluated contrast sensitivity used the drug acitretin, the results of which are consistent with those the present study.

Conclusion: Our study is significant in that it is the first to investigate the effects of isotretinoin on visual contrast sensitivity that is closely associated with real-world performance. Our results need to be supported by future studies.     

口服异维A酸治疗扁平疣疗效观察

目的：观察异维A酸治疗扁平疣的疗效、副作用。方法：口服异维A酸10mg，3次／d，两周后改用10mg，2次／d。结果：总有效率88，4％。结论：异维A酸是治疗扁平疣的有效药物，且药量小，副作用小。     

An evaluation of peripapillar choroidal thickness in patients receiving systemic isotretinoin treatment

Purpose: Oral isotretinoin (13-cis retinoic acid, 13-cis RA) was approved for severe acne treatment by the FDA in 1982. The ocular side effects associated with oral isotretinoin use are mostly dose-dependent. Numerous ocular pathologies affect peripapillary choroidal layer primarily or indirectly.

Objective: Evaluation of the peripapillary choroidal layer in the patients receiving oral isotretinoin therapy may aid in explaining the pathophysiology of ocular side effects.

Methods: In this study, peripapillary choroidal thickness was assessed in the patients receiving oral isotretinoin treatment via optical coherent tomography technique.

Results: Significant difference was found in the superotemporal and temporal areas.

Conclusion: Oral isotretinoin treatment may affect the thickness of the peripapillary choroidal layer.     

The frequency of hematuria in acne vulgaris patients during isotretinoin treatment

Background: Systemic isotretinoin (13-cis-retinoic acid) is effective in the treatment of acne vulgaris. The most common side effects are mucocutaneous ones. Hematuria seen secondary to isotretinoin treatment is thought to be due to mucosal dryness in the urinary system. This study aims to determine the frequency of hematuria in acne vulgaris patients during isotretinoin treatment.

Materials and method: Eighty-eight subjects aged 16–32 years were included in the study group and 52 subjects were in the control group. The subjects were treated for 6 months and were monitored monthly by complete urine analyzes. They were also examined each month in terms of cheilitis, xerosis, epistaxis, rectal bleeding, fatigue, myalgia, weight loss, dry eye, conjunctivitis, headache, dysuria and pollakiuria.

Results: In the study group, 15 subjects (17%) had hematuria at least once during the study, and in the control group, four subjects (7.7%) had hematuria. The difference was not statistically significant (p?=?0.118). Among the subjects who had hematuria, 11 of them (73.3%) were female and four of them (33.3%) were male in the study group while all the subjects with hematuria in the control group were female. Hematuria and gender did not show a statistically significant correlation.

Conclusion: Hematuria was observed in 17% of the study group; this frequency rate was not different from that of the normal population. In subjects having isotretinoin treatment, if all the other reasons or disorders are excluded, one must keep in mind that hematuria may be due to isotretinoin use.     

The long-term effect of oral isotretinoin therapy on macula ganglion cell complex thickness

Purpose: To evaluate the long-term effect of oral isotretinoin therapy on macula ganglion cell complex (GCC) thickness by spectral domain optical coherence tomography (SD-OCT).

Materials and methods: Newly diagnosed cystic acne patients who received low dose for a long time systemic isotretinoin therapy were included in this study. Thorough ophthalmic evaluation and GCC thickness analysis by using SD-OCT were performed at baseline, and at 1, 3, 6, and 12 months of treatment.

Results: Forty-eight eyes of 24 patients (15 females, 9 males) were included in the study. The mean age of patients was 19.37?±?2.74 years (range 14–25 years). The full ophthalmologic examination was normal in all eyes before treatment. During the treatment there were no change in visual acuity, refractive error, intraocular pressure and tear break-up time. The mean GCC thicknesses were 81.45?±?4.91, 81.45?±?5.12, 81.81?±?4.68, 81.87?±?4.91 and 81.64?±?5.09?μm at pretreatment and at 1, 3, 6, and 12 months of treatment, respectively (p?=?0.803).

Conclusion: One-year systemic use of isotretinoin had no significant effect on the thickness of macula ganglion cell. Macular ganglion cell analysis is useful for determining and following the toxic effects of systemic drugs on the retina. However, it is more rational to consider it as an adjunct to electrophysiological testing rather than used alone.     

FDA对异维A酸事件实施风险干预的案例研究

文中通过学习FDA《风险最小化行动计划的执行与应用》,分析了FDA对异维A酸事件的特殊风险干预措施,FDA根据RiskMAP对异维A酸采取了iPLEDGE这一强制型风险管理计划,对我国处理类似事件具有重要的借鉴意义,为提高我国今后对药品安全风险的干预能力提供了支持。     

HPLC法测定维A酸与异维A酸含量

目的:建立HPLC法测定维A酸和异维A酸的含量方法。方法:采用Kromasil C_(18)(4.6mm×250mm,5μm)色谱柱,以甲醇-水-冰醋酸(90∶10∶0.5)为流动相,流速为1.0mL·min~(-1),柱温为30℃,检测波长为358nm。进样量20μL。结果:维A酸在4.4～17.4μg·mL~(-1)范围内线性关系良好,回归方程为A=8.127×10~3C 8.5698×10~2(r=0.9997),平均回收率为99.1%(RSD=0.7%)。异维A酸在1.083～4.332μg·mL~(-1)范围内线性关系良好,回归方程为A=103.73C 2.4(r=0.9999),平均回收率为100.1%(RSD=0.6%)。结论:该方法快速、准确,灵敏度高,重复性好,而且与其他降解产物能较好的分离。     

Evaluation of sequential effect of isotretinoin on the haematological parameters in patients with acne vulgaris

Purpose: Isotretinoin is the most effective drug for acne with some side effects. Few studies exist regarding the effects of isotretinoin on haematological parameters with different results. Mostly, baseline values with a single value during or at the end of the treatment were compared. In this study, we aimed to determine the differences in haematological parameters during isotretinoin treatment until reaching the cumulative dose of 120?mg/kg.

Materials and methods: The study included 118 patients with moderate-to-severe acne vulgaris. Patients with preexisting liver disease, anaemia, iron deficiency, abnormal liver function tests, thrombocytopenia/thrombocytosis or hyperlipidaemia were excluded. Laboratory monitoring for haematological parameters was performed at baseline and monthly during treatment. Parameters at the baseline, at the first and second months and at the end of the therapy were taken into account.

Results: According to general linear model analysis, platelets and plateletcrit increased at the first month of the treatment and then decreased to baseline. White blood cells and neutrophils decreased at the first month, then increased to baseline value at the second month, and were found to be decreased again at the end of the treatment. Mean corpuscle volume was found to be increased at the end of the treatment. Other parameters in CBC did not show statistically significant differences.

Conclusions: Although some changes occur in haematological parameters during isotretinoin therapy, all of these changes remain within the normal range. Evaluating the spot values at any time during treatment may cause misinterpretations.     

常用药物对男性生育力影响的研究进展

为临床遴选男性患者治疗药物提供一定参考,以避免选用对男性生育力存在不利影响的药物。本文就近年已有研究可能对男性生育力存在不利影响的药物进行归纳和总结。目前有关药物对男性生殖系统影响的研究较少,但从现有研究中发现,包括外源性睾酮、5-α还原酶抑制剂、抗抑郁药、抗癫痫药及抗菌药物等在内的多种药物均可能对男性生育力产生不利影响。许多常用药物均可对男性生育力产生不同程度的损害,临床医生为男性患者遴选治疗药物时需在一定程度上考虑到该因素。但现有有关药物对男性生育力影响的研究仍较少,故仍需更多临床试验加以关注和验证。     

The impact of chemotherapy on male fertility: a survey of the biologic basis and clinical aspects

The introduction of cisplatin-based polychemotherapy has led to cure rates of up to 90% for the most frequent malignant diseases seen in young men. In view of these high cure rates, increasing clinical importance is now being attached to chemotherapy-induced fertility disorders. Comparative studies examining the impact of cytotoxic chemotherapy on gametogenesis demonstrate significant cytostatic- and dose-specific differences. The extensive literature on possible teratogenic effects of chemotherapy provides no evidence suggesting that offspring of patients with a history of chemotherapy have an increased risk of malformations. However, these studies, the scope and follow-up of which may still be inadequate, have failed to eliminate the fear of such risk. Hormonal protection from chemotherapy-induced testicular damage has thus far succeeded only in animal models pretreated by application of gonadotropin-releasing hormone agonists combined with nonsteroidal antiandrogens or testosterone plus 17β-estradiol. The same holds true for hormone therapy aimed at stimulating the recovery of spermatogenesis after chemotherapy-induced testicular damage. Cryopreservation of germ cells can be suggested to patients undergoing cytostatic therapy. In some cases, testicular extraction of spermatozoa can also be offered as a novel approach.     

An unusual side effect of isotretinoin: retinoid dermatitis affecting external urethral meatus

Isotretinoin (Iso) is the most effective drug against severe nodulocystic acne. As a synthetic oral retinoid, Iso exerts its actions by modulating cell growth and differentiation. Targeting all the pathophysiologic processes in acne development, Iso has been considered to be an unique drug, however it has several side effects. While chelitis, xerosis, ocular sicca, arthralgia, myalgia, headache, hyperlipidemia are the most common side effects, teratogenicity and depressive symptoms are the most concerning ones. In addition, Iso has unusual side effects which have been described for the first time in the literature. Here, we report a remarkable side effect of Iso in a 23-years-old male patient with retinoid dermatitis affecting the external uretral meatus. To our knowledge, only few cases of retinoid dermatitis in the urethral mucosa due to Iso have been reported in the literature so far.     

Pityriasis rosea-like eruption induced by isotretinoin

Pityriasis rosea is a common, self-limited and inflammatory skin disease. The etiology is not clearly known. Viral agents, autoimmunity, psychogenic factors and drugs have all been suggested as risk factors. Isotretinoin is usually used in the treatment of resistant, nodulocytic acne. We present a case of pityriasis rosea-like eruption induced by isotretinoin. To our knowledge, this is the second clinical case of pityriasis rosea-like eruption induced by isotretinoin.     

The prevalence of sacroiliitis in patients with acne vulgaris using isotretinoin

Background/Objective: Acne vulgaris is a chronic inflammatory disease affecting the pilosebaceous unit in the skin. Isotretinoin is a synthetic vitamin A derivative regarded as the most effective agent in the treatment of acne. There have recently been increasing reports of adverse effects of isotretinoin on the skeletal system. Our aim in this study was to evaluate the rheumatic side-effects triggered by this drug, and particularly the prevalence of sacroiliitis.

Materials and methods: A total of 73 patients receiving isotretinoin due to moderate or severe acne vulgaris were included. All patients were questioned about inflammatory low back pain and musculoskeletal pains during the treatment process. Inflammatory low back pain was evaluated using Assessment of Spondyloarthritis International Society (ASAS) criteria. Patients meeting ASAS criteria were evaluated with radiography and when necessary with sacroiliac magnetic resonance.

Results: The dose range for isotretinoin was between 0.4 and 0.8?mg/kg/day (mean 0.53?mg/kg/day). Treatment lasted for 6–8 months (mean 6.8 months). Lethargy was determined in 37 (50.7%) patients, myalgia in 31 (42.5%) and low back pain in 36 (49.3%). Mechanical low back pain symptoms were present in 20 of the patients describing low back pain and inflammatory low back pain in 16. Acute sacroiliitis was determined in six patients (8.2%) following a sacroiliac magnetic resonance imaging (MRI). Five (83.3%) of the patients with sacroiliitis were female and one (16.7%) was male. No statistically significant difference was determined between male and female patients in terms of prevalence of sacroiliitis (p =?0.392).

Conclusion: The incidence of sacroiliitis in patients using isotretinoin is quite high. Patients using isotretinoin must be questioned about sacroiliitis findings and must be subjected to advanced assessment when necessary. Further studies regarding the development of sacroiliitis under isotretinoin therapy are now needed.     

The effect of alkylating agents on male rat fertility

The effects of tumour inhibitory doses of tretamine (triethylenemelamine), busulphan, and melphalan on the fertility of male rats have been examined. The aromatic nitrogen mustard, melphalan, was inactive, but busulphan has a highly selective action on spermatogenesis which contrasts strikingly with that of tretamine. The main action of tretamine was exerted upon spermatocytes or spermatids, but, with increasing dose, the effects spread to involve a wide range of spermatogenic cells including mature sperm, so that infertility could be induced very rapidly. Busulphan, however, interfered with the development of spermatogonia for several weeks, although other germinal cells were unaffected and continued to develop into mature spermatozoa. This accounted for the continuation of normal fertility for 7 weeks after a dose, before sterility suddenly developed. The antifertility activity of tretamine could be simulated by a variety of other ethyleneimino compounds, potency being greatest in trifunctional and least in monofunctional compounds. The latter were, however, very destructive to the seminiferous epithelium with increasing dose. In the rat, there appeared to be no definite relationship between the ability of alkylating substances to interfere with the activity of normal and pathological proliferating tissues, as represented by the germinal epithelium, haematopoietic, and tumour tissue. Although carcinogenicity was a biological property of alkylating agents, other chemical types of carcinogen did not interfere with fertility.     

异维A酸胶丸治疗结节囊肿性痤疮196例的疗效

目的：观察异维A酸胶丸治疗结节囊肿性痤疮的临床疗效。方法：选择门诊痤疮患者326例进行治疗,随机分成试验组和对照组。试验组196例,口服异维A酸胶丸,剂量0.4mg.kg^-1.d^-1,bid;对照组130例,口服红霉素12mg.kg^-1.d^-1,bid。两组均给药12周后观察疗效。结果：试验组有效率显著高于对照组（73.47%vs48.46%,P〈0.05）。两组均无明显不良反应发生。结论：异维A酸胶丸治疗结节囊肿性痤疮疗效确切。     

Effects of isotretinoin on the inflammatory markers and the platelet counts in patients with acne vulgaris

Objective: Oral isotretinoin is an efficient treatment used commonly in treating the moderate and severe acne. It has various side effects that affect many systems in the body. In this study, we are planning to examine the possible effects of the oral isotretinoin on platelet density, mean platelet volume, neutrophil lymphocyte rate, platelet lymphocyte rate, and red-blood-cell distribution width level.

Methods: Twenty-eight males and 84 females, 112 patients in total, diagnosed with acne vulgaris and receiving oral isotretinoin treatment were examined retrospectively. The full blood parameters of the patients before the treatment and in the third month of the treatment were recorded.

Results: A statistically meaningful increase was observed in the platelet density, hemoglobin levels. And a statistically significant decrease has been determined in the red-blood-cell distribution width level while no meaningful differences were detected in the mean platelet volume, neutrophil lymphocyte rate, platelet lymphocyte rate, and white blood cell count.

Conclusions: The oral isotretinoin treatment has been demonstrated as having increased the platelet density, hemoglobin levels and having decreased red-blood-cell distribution width level significantly.     

Impairment of male fertility induced by muscarinic receptor antagonists in rats

Male rats were treated with a muscarinic receptor antagonist at 3, 10, and 100 mg/kg/day for 4 weeks prior to mating with untreated females and their reproductive status was determined on gestation days (GD) 15–17. Treatment-related decreases in the pregnancy rate were observed at 100 mg/kg/day without any effects on mating performance. Impairment of male fertility by this compound was also observed after treatment for 1 week, but there were no effects after a 1-week withdrawal period suggesting reversibility of the effect. There were no treatment-related effects on sperm production or motility, or testicular histopathology in any group. In order to determine whether the reduced fertility was a class effect of muscarinic receptor antagonists, atropine was examined. Males received atropine for 1 week at 62.5 and 125 mg/kg/day and were mated with untreated females. A low pregnancy rate associated with a decrease in the number of implantations was observed at 125 mg/kg/day. The effect on implantation was also observed at 62.5 mg/kg/day. These findings suggest that the impairment of fertility in male rats induced by muscarinic receptor antagonists is a class effect, and has a relatively short onset of effect and is quickly reversible.     

异维A酸联合克林霉素凝胶治疗痤疮的疗效观察

目的：观察口服异维A酸与外用克林霉素磷酸酯凝胶联合治疗面部中度寻常痤疮的疗效。方法：将136例中度痤疮患者随机分为两组,治疗组70例采用口服异维A酸联合外用克林霉素磷酸酯凝胶治疗8wk;对照组单用克林霉素磷酸酯凝胶治疗8wk。结果：治疗组的总有效率为84．29％;对照组的总有效率为39．39％。经卡方检验,两组有极显著性差异（P〈0．01）。结论：口服异维A酸联合外用克林霉素磷酸酯凝胶是治疗中度寻常痤疮的有效方法。