Original Article Received: November 11, 2014 Accepted after revision: December 13, 2014 Published online: January 30, 2015
Gynecol Obstet Invest DOI: 10.1159/000371551
The Effect of Isotretinoin on Ovarian Reserve Based on Hormonal Parameters, Ovarian Volume, and Antral Follicle Count in Women with Acne Huseyin Aksoy a Levent Cinar b Gokhan Acmaz c Ulku Aksoy f Turgut Aydin g Umit Erkan Vurdem d Leyla Oz e Ozge Idem Karadag g Demet Kartal b
a
Department of Obstetrics and Gynecology, Kayseri Military Hospital, b Department of Dermatology, Erciyes University Faculty of Medicine, Departments of c Obstetrics and Gynecology, d Radiology and e Biochemistry, Kayseri Education and Research Hospital of Medicine, f Department of Obstetrics and Gynecology, Kayseri Memorial Hospital, and g Department of Obstetrics and Gynecology, Kayseri Acıbadem Hospital, Kayseri, Turkey
Abstract Backgroud/Aims: Widely prescribed in routine practice, isotretinoin has an unknown impact on ovarian reserve. With a long history in acne treatment and numerous potential side effects, it is surprising that very few prospective studies have investigated its effect on ovarian reserve. Therefore, we aimed to evaluate the impact of oral isotretinoin on ovarian reserve based on hormonal parameters, anti-Müllerian hormone (AMH), ovarian volume (OV), and antral follicle count (AFC) in women of reproductive age with acne. Methods: Our study group consisted of 82 women of reproductive age with acne who were treated with oral isotretinoin. The patients were evaluated for ovarian reserve prior to therapy and reevaluated 6 months after isotretinoin treatment with regard to hormonal parameters, AMH, OV, and AFC. Results: Significant differences were found between the pre- and posttreatment period for AMH [2.20 ng/ml (25th–75th percentile 1.14– 4.07) vs. 1.31 ng/ml (0.32–2.28)], total AFC [16 (14–18.25) vs. 12.5 (10–15)], and total OV [23 ml (18–29) vs. 15 ml (13–18); p < 0.001]. Conclusion: Our study is the first to analyze the
© 2015 S. Karger AG, Basel 0378–7346/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/goi
levels of serum AMH, AFC, and OV together in patients treated with oral isotretinoin for acne. The results of our study demonstrated that oral isotretinoin had a significant negative effect on ovarian reserve. © 2015 S. Karger AG, Basel
Introduction
The treatment of choice for acne vulgaris is oral isotretinoin, a common and efficacious remedy which has been used for many years. It reduces sebum secretion and inhibits bacterial proliferation, leading to shrinkage of the acne [1]. While approved by the Food and Drug Administration for severe, recalcitrant, and nodular acne, isotretinoin has many additional indications, such as for treatment-resistant acne, scarring acne, and acne that causes significant psychological distress [2]. On the other hand, all-trans retinoic acid (RA) is used in the initial treatment of acute promyelocytic leukemia and has a critical role in promoting malignant promyelocytes to mature neutrophils [3]. In other words, isotretinoin is a well-known chemotherapeutic agent used as a first-line treatment of acute promyelocytic leukemia. We are of the opinion that there are some rising concerns about the use of isotretiHuseyin Aksoy, MD Department of Obstetrics and Gynecology Kayseri Military Hospital TR–38050 Kayseri (Turkey) E-Mail drhuseyinaksoy77 @ hotmail.com
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 2/15/2015 5:50:22 PM
Key Words Acne · Anti-müllerian hormone · Antral follicle count · Isotretinoin · Ovarian volume
Materials and Methods This study was approved by the Institutional Review Board and the Ethics Committee of the Erciyes University School of Medicine, and all participants signed an informed consent to participate. This prospective study was performed between March 2013 and March 2014 at the Kayseri Education and Research Hospital of Medicine, a tertiary referral center in Turkey. Our study group consisted of 121 women of reproductive age who attended our dermatology clinic for the treatment of acne. All patients who met the eligibility criteria were sequentially recruited by our research coordinator (L.C.). The final study group was composed of 82 women. The patients were evaluated for ovarian reserve prior to therapy and reevaluated 6 months after isotretinoin treatment. The women allocated to this study had regular menstrual cycles and normal ovarian morphologies, confirmed by ultrasonography. None were pregnant, and we did not administer progesterone for withdrawal bleeding. All patients received oral isotretinoin for 6 months with the indication of acne. Participants were excluded based on the following criteria: menstrual irregularity, polycystic ovary syndrome, thyroid disorders, hypertension, thromboembolic disease, diabetes mellitus, cardiovascular events, Cushing’s disease, positive malignancy, congenital adrenal hyperplasia, liver disease, psychotic disorders, and the use of antidepressants, steroidal hormone drugs, mood stabilizers, caffeine, alcohol, or tobacco. Moreover, participants with histories of abdominal surgery for endometriosis or ovarian surgery were excluded. Each participant underwent a comprehensive systemic and pelvic examination to exclude systemic and pelvic pathologies, and sociodemographic and medical information was collected. To establish baseline values, on days 2–5 of the menstrual cycle, venous blood samples for hormonal assay and other biochemical parameters were obtained in the morning after an overnight fast. After immediate transport to the laboratory, the samples were centrifuged for 10 min
2
Gynecol Obstet Invest DOI: 10.1159/000371551
at 3,000 rpm and then stored at –80 ° C until assayed. Serum AMH concentrations were determined using an enzyme-linked immunosorbent assay kit (Beckman Coulter, Brea, Calif., USA). Serum free triiodothyronine, free thyroxine, thyroid-stimulating hormone, FSH, LH, E2, and total testosterone levels were analyzed using an automated chemiluminescence system (Unicell DxI 800; Beckman Coulter). Hemoglobin, platelet, and white blood cell concentrations were measured using an automatic hematology analyzer (BC-6800; Mindray, China). Serum AST, ALT, blood urea nitrogen, creatinine, and glucose concentrations were measured using an autoanalyzer (Olympus AU-2700; Beckman Coulter). Serum free testosterone levels were analyzed using radioimmunoassay (DSL; Beckman Coulter). The erythrocyte sedimentation rates were determined using the Westergren method (Alifax SPA, Adova, Italy). Sensitivity, specificity, and inter- and intra-assay coefficients of variation were within the limits provided by the manufacturers. The participants underwent ultrasonographic pelvic assessments on the same day using a Toshiba Xario (Toshiba Medical Systems Corporation, Japan) equipped with a curved array transducer and a 3.5- to 5-MHz convex probe. The number of antral follicles measuring 2–10 mm in diameter was counted, and the OV was measured as previously described [8]. All ultrasound measurements were performed by a single experienced radiologist (U.E.V.) who was blinded to all patient data. The patients were treated with 0.6–0.8 mg/kg oral isotretinoin up to a total dose of 120–150 mg/kg. Treatment was started at 20 mg/day and gradually increased to the maximum of 40 mg/day. The patients were monitored monthly during isotretinoin treatment. Hormonal and biochemical parameters and ultrasound examinations were repeated after 6 months. The controls were also examined after 6 months according to the same criteria.
Statistics To test for normality, the Shapiro-Wilk test was used, and variance homogeneity was confirmed using Levene’s test. Values are expressed as means ± standard deviation or medians (25th–75th percentile). Paired sample t tests or related sample Wilcoxon signed-rank tests were performed to evaluate differences between groups. All calculations were made using PASW Statistics 18 software (SPSS, Chicago, Ill., USA).
Results
Of the 121 participants enrolled, 84 met the inclusion criteria and 37 were eliminated by the exclusion criteria. We excluded 9 participants who had polycystic ovary syndrome, 8 who had diabetes mellitus, 6 who used combined oral contraceptives, 5 who had thyroid disease, 2 who had had previous surgery, and 7 who used tobacco. Additionally, 2 were lost to follow-up. The final study group was composed of 82 subjects. The mean age was 21.14 ± 4.12 years (range 18–36). Seventy-three (89.02%) were nulliparous, 6 (7.31%) were multiparous, and 3 (3.65%) were primiparous. The majority (55, 67%) were single. Only 27 (33%) were married. BaseAksoy /Cinar /Acmaz /Aksoy /Aydin / Vurdem /Oz /Idem Karadag /Kartal
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 2/15/2015 5:50:22 PM
noin by women of reproductive age with depleted ovarian reserve [4, 5], and, therefore, it is important to detect the effect of isotretinoin on ovarian reserve. The serum anti-Müllerian hormone (AMH) level can correctly indicate ovarian reserve in young women after treatment for childhood cancer with chemotherapy and radiotherapy [6]. Additional ways to determine ovarian reserve in humans include measures of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), antral follicle count (AFC), and ovarian volume (OV) [7]. Widely and commonly prescribed in routine dermatological practice, isotretinoin has an unknown impact on ovarian reserve. With a long history in acne treatment and numerous potential side effects, it is surprising that very few prospective studies have investigated its effect on ovarian reserve. Therefore, we aimed to evaluate the impact of oral isotretinoin on ovarian reserve in women of reproductive age.
Table 1. Baseline biochemical parameters before and after treatment (n = 82)
Parameters
Before treatment
After treatment
Hgb, g/dl PLT, ×10³/μl WBC, ×10³/μl AST, U/l ALT, U/l BUN, mg/dl Creatinine, mg/dl Glucose, mg/dl ESR, mm/h FT3, pg/ml FT4, ng/dl TSH, mIU/l
13.8 (12.8 – 13.5) 284,000 (242,000 – 326,250) 7.2 (6.23 – 8.81) 20 (17 – 22) 15 (14 – 18) 9 (8 – 11) 6 (5 – 6) 88.33 ± 8.24 8 (4.75 – 11) 3.2 (2.94 – 3.37) 0.88 (0.81 – 1) 1.77 (1.24 – 2.35)
13.25 (12.8 – 14) 282,000 (241,000 – 311,000) 7.49 (6.17 – 8.46) 23 (21 – 31) 20 (18 – 28.25) 12 (10 – 15) 6 (6 – 7) 86.18 ± 8.49 11 (9 – 18) 3.14 (2.99 – 3.34) 0.9 (0.79 – 1.11) 1.91 (1.22 – 2.43)
p
Gynecol Obstet Invest DOI: 10.1159/000371551
The Effect of Isotretinoin on Ovarian Reserve Based on Hormonal Parameters, Ovarian Volume, and Antral Follicle Count in Women with Acne Huseyin Aksoy a Levent Cinar b Gokhan Acmaz c Ulku Aksoy f Turgut Aydin g Umit Erkan Vurdem d Leyla Oz e Ozge Idem Karadag g Demet Kartal b
a
Department of Obstetrics and Gynecology, Kayseri Military Hospital, b Department of Dermatology, Erciyes University Faculty of Medicine, Departments of c Obstetrics and Gynecology, d Radiology and e Biochemistry, Kayseri Education and Research Hospital of Medicine, f Department of Obstetrics and Gynecology, Kayseri Memorial Hospital, and g Department of Obstetrics and Gynecology, Kayseri Acıbadem Hospital, Kayseri, Turkey
Abstract Backgroud/Aims: Widely prescribed in routine practice, isotretinoin has an unknown impact on ovarian reserve. With a long history in acne treatment and numerous potential side effects, it is surprising that very few prospective studies have investigated its effect on ovarian reserve. Therefore, we aimed to evaluate the impact of oral isotretinoin on ovarian reserve based on hormonal parameters, anti-Müllerian hormone (AMH), ovarian volume (OV), and antral follicle count (AFC) in women of reproductive age with acne. Methods: Our study group consisted of 82 women of reproductive age with acne who were treated with oral isotretinoin. The patients were evaluated for ovarian reserve prior to therapy and reevaluated 6 months after isotretinoin treatment with regard to hormonal parameters, AMH, OV, and AFC. Results: Significant differences were found between the pre- and posttreatment period for AMH [2.20 ng/ml (25th–75th percentile 1.14– 4.07) vs. 1.31 ng/ml (0.32–2.28)], total AFC [16 (14–18.25) vs. 12.5 (10–15)], and total OV [23 ml (18–29) vs. 15 ml (13–18); p < 0.001]. Conclusion: Our study is the first to analyze the
© 2015 S. Karger AG, Basel 0378–7346/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/goi
levels of serum AMH, AFC, and OV together in patients treated with oral isotretinoin for acne. The results of our study demonstrated that oral isotretinoin had a significant negative effect on ovarian reserve. © 2015 S. Karger AG, Basel
Introduction
The treatment of choice for acne vulgaris is oral isotretinoin, a common and efficacious remedy which has been used for many years. It reduces sebum secretion and inhibits bacterial proliferation, leading to shrinkage of the acne [1]. While approved by the Food and Drug Administration for severe, recalcitrant, and nodular acne, isotretinoin has many additional indications, such as for treatment-resistant acne, scarring acne, and acne that causes significant psychological distress [2]. On the other hand, all-trans retinoic acid (RA) is used in the initial treatment of acute promyelocytic leukemia and has a critical role in promoting malignant promyelocytes to mature neutrophils [3]. In other words, isotretinoin is a well-known chemotherapeutic agent used as a first-line treatment of acute promyelocytic leukemia. We are of the opinion that there are some rising concerns about the use of isotretiHuseyin Aksoy, MD Department of Obstetrics and Gynecology Kayseri Military Hospital TR–38050 Kayseri (Turkey) E-Mail drhuseyinaksoy77 @ hotmail.com
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 2/15/2015 5:50:22 PM
Key Words Acne · Anti-müllerian hormone · Antral follicle count · Isotretinoin · Ovarian volume
Materials and Methods This study was approved by the Institutional Review Board and the Ethics Committee of the Erciyes University School of Medicine, and all participants signed an informed consent to participate. This prospective study was performed between March 2013 and March 2014 at the Kayseri Education and Research Hospital of Medicine, a tertiary referral center in Turkey. Our study group consisted of 121 women of reproductive age who attended our dermatology clinic for the treatment of acne. All patients who met the eligibility criteria were sequentially recruited by our research coordinator (L.C.). The final study group was composed of 82 women. The patients were evaluated for ovarian reserve prior to therapy and reevaluated 6 months after isotretinoin treatment. The women allocated to this study had regular menstrual cycles and normal ovarian morphologies, confirmed by ultrasonography. None were pregnant, and we did not administer progesterone for withdrawal bleeding. All patients received oral isotretinoin for 6 months with the indication of acne. Participants were excluded based on the following criteria: menstrual irregularity, polycystic ovary syndrome, thyroid disorders, hypertension, thromboembolic disease, diabetes mellitus, cardiovascular events, Cushing’s disease, positive malignancy, congenital adrenal hyperplasia, liver disease, psychotic disorders, and the use of antidepressants, steroidal hormone drugs, mood stabilizers, caffeine, alcohol, or tobacco. Moreover, participants with histories of abdominal surgery for endometriosis or ovarian surgery were excluded. Each participant underwent a comprehensive systemic and pelvic examination to exclude systemic and pelvic pathologies, and sociodemographic and medical information was collected. To establish baseline values, on days 2–5 of the menstrual cycle, venous blood samples for hormonal assay and other biochemical parameters were obtained in the morning after an overnight fast. After immediate transport to the laboratory, the samples were centrifuged for 10 min
2
Gynecol Obstet Invest DOI: 10.1159/000371551
at 3,000 rpm and then stored at –80 ° C until assayed. Serum AMH concentrations were determined using an enzyme-linked immunosorbent assay kit (Beckman Coulter, Brea, Calif., USA). Serum free triiodothyronine, free thyroxine, thyroid-stimulating hormone, FSH, LH, E2, and total testosterone levels were analyzed using an automated chemiluminescence system (Unicell DxI 800; Beckman Coulter). Hemoglobin, platelet, and white blood cell concentrations were measured using an automatic hematology analyzer (BC-6800; Mindray, China). Serum AST, ALT, blood urea nitrogen, creatinine, and glucose concentrations were measured using an autoanalyzer (Olympus AU-2700; Beckman Coulter). Serum free testosterone levels were analyzed using radioimmunoassay (DSL; Beckman Coulter). The erythrocyte sedimentation rates were determined using the Westergren method (Alifax SPA, Adova, Italy). Sensitivity, specificity, and inter- and intra-assay coefficients of variation were within the limits provided by the manufacturers. The participants underwent ultrasonographic pelvic assessments on the same day using a Toshiba Xario (Toshiba Medical Systems Corporation, Japan) equipped with a curved array transducer and a 3.5- to 5-MHz convex probe. The number of antral follicles measuring 2–10 mm in diameter was counted, and the OV was measured as previously described [8]. All ultrasound measurements were performed by a single experienced radiologist (U.E.V.) who was blinded to all patient data. The patients were treated with 0.6–0.8 mg/kg oral isotretinoin up to a total dose of 120–150 mg/kg. Treatment was started at 20 mg/day and gradually increased to the maximum of 40 mg/day. The patients were monitored monthly during isotretinoin treatment. Hormonal and biochemical parameters and ultrasound examinations were repeated after 6 months. The controls were also examined after 6 months according to the same criteria.
Statistics To test for normality, the Shapiro-Wilk test was used, and variance homogeneity was confirmed using Levene’s test. Values are expressed as means ± standard deviation or medians (25th–75th percentile). Paired sample t tests or related sample Wilcoxon signed-rank tests were performed to evaluate differences between groups. All calculations were made using PASW Statistics 18 software (SPSS, Chicago, Ill., USA).
Results
Of the 121 participants enrolled, 84 met the inclusion criteria and 37 were eliminated by the exclusion criteria. We excluded 9 participants who had polycystic ovary syndrome, 8 who had diabetes mellitus, 6 who used combined oral contraceptives, 5 who had thyroid disease, 2 who had had previous surgery, and 7 who used tobacco. Additionally, 2 were lost to follow-up. The final study group was composed of 82 subjects. The mean age was 21.14 ± 4.12 years (range 18–36). Seventy-three (89.02%) were nulliparous, 6 (7.31%) were multiparous, and 3 (3.65%) were primiparous. The majority (55, 67%) were single. Only 27 (33%) were married. BaseAksoy /Cinar /Acmaz /Aksoy /Aydin / Vurdem /Oz /Idem Karadag /Kartal
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 2/15/2015 5:50:22 PM
noin by women of reproductive age with depleted ovarian reserve [4, 5], and, therefore, it is important to detect the effect of isotretinoin on ovarian reserve. The serum anti-Müllerian hormone (AMH) level can correctly indicate ovarian reserve in young women after treatment for childhood cancer with chemotherapy and radiotherapy [6]. Additional ways to determine ovarian reserve in humans include measures of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), antral follicle count (AFC), and ovarian volume (OV) [7]. Widely and commonly prescribed in routine dermatological practice, isotretinoin has an unknown impact on ovarian reserve. With a long history in acne treatment and numerous potential side effects, it is surprising that very few prospective studies have investigated its effect on ovarian reserve. Therefore, we aimed to evaluate the impact of oral isotretinoin on ovarian reserve in women of reproductive age.
Table 1. Baseline biochemical parameters before and after treatment (n = 82)
Parameters
Before treatment
After treatment
Hgb, g/dl PLT, ×10³/μl WBC, ×10³/μl AST, U/l ALT, U/l BUN, mg/dl Creatinine, mg/dl Glucose, mg/dl ESR, mm/h FT3, pg/ml FT4, ng/dl TSH, mIU/l
13.8 (12.8 – 13.5) 284,000 (242,000 – 326,250) 7.2 (6.23 – 8.81) 20 (17 – 22) 15 (14 – 18) 9 (8 – 11) 6 (5 – 6) 88.33 ± 8.24 8 (4.75 – 11) 3.2 (2.94 – 3.37) 0.88 (0.81 – 1) 1.77 (1.24 – 2.35)
13.25 (12.8 – 14) 282,000 (241,000 – 311,000) 7.49 (6.17 – 8.46) 23 (21 – 31) 20 (18 – 28.25) 12 (10 – 15) 6 (6 – 7) 86.18 ± 8.49 11 (9 – 18) 3.14 (2.99 – 3.34) 0.9 (0.79 – 1.11) 1.91 (1.22 – 2.43)
p
