J Pediatr Endocr Met 2015; aop
Hiba Al-Zubeidi and Karen O. Klein*
Randomized clinical trial evaluating metformin versus oral contraceptive pills in the treatment of adolescents with polycystic ovarian syndrome Abstract
Introduction
Background: Polycystic ovarian syndrome (PCOS) is characterized by irregular menses, elevated androgens, and insulin resistance. Little information is published about the treatment of adolescent PCOS. Objectives: The aim of this study was to evaluate metformin versus oral contraceptive pills (OCP) in treating adolescent PCOS. Twenty-two girls were randomized to either treatment for 6 months. The outcomes variables included body mass index (BMI) and free testosterone (FT). Results: BMI decreased in all patients (metformin p = 0.004, OCP p = 0.045). FT decreased significantly only with OCP. Insulin resistance measures decreased in all patients but did not reach significance. The only significant difference in any of the variables between the two groups was number of menses. BMI and FT remained less than baseline for 3 months off treatment. Conclusions: Metformin and OCP have a positive effect on BMI, which persists after treatment is discontinued. FT decreased with both treatments, but only reached significance with OCP. Keywords: adolescent polycystic ovarian syndrome; hyperandrogenism; irregular menses; metformin; oral contraceptives. DOI 10.1515/jpem-2014-0283 Received July 2, 2014; accepted January 23, 2015
*Corresponding author: Karen O. Klein, MD, Rady Children’s Hospital San Diego, San Diego, CA, USA; Department of Pediatrics Endocrinology, University of California, San Diego, CA, USA, Phone: +858-966-4032, Fax: +858-966-6227, E-mail: [email protected] Hiba Al-Zubeidi: Le Bonheur Children’s Hospital, Memphis, Tennessee, Department of Pediatric Endocrinology, University of Tennessee Health Science Center, Memphis, TN
Polycystic ovarian syndrome (PCOS) is the most common metabolic disorder in women of reproductive age. The estimated prevalence varies depending on the diagnostic criteria used. In adult women, the prevalence in several studies identified PCOS with a prevalence of 4%–12% (1– 3). In some European studies, the prevalence of PCOS has been reported to be 6.5%–8% (4). In adolescents, accurate data about the incidence and prevalence of PCOS is scant with higher incidence associated with obesity (5–8) and in first-degree relatives and patients with a history of premature adrenarche (9, 10). PCOS is primarily characterized by ovulatory dysfunction and hyperandrogenism. Insulin resistance or obesity, both commonly associated with this disorder appears to further amplify the severity of the presentation (11). The pathophysiology of PCOS has not been fully characterized. Many patients have evidence of abnormal luteinizing hormone (LH) secretion in which patients have higher serum concentrations and increased frequency and amplitude of LH pulses. A significant percentage of patients with PCOS display insulin resistance. The combination of insulin resistance and increased LH secretion appears to stimulate ovarian androgen production. In addition, elevated insulin levels inhibit hepatic synthesis of sex hormone binding globulin (SHBG) (11, 12). These changes result in increased bioavailability of free androgens. Excess androgen production in PCOS patients has been shown to cause premature ovarian follicle arrest leading to anovulation and menstrual irregularities (11–15). Thus, the combination of elevated LH, hyperinsulinemia, and ovarian androgen production produces the PCOS phenotype of oligoovulation and hyperandrogenism. Treating PCOS in adolescents is important beyond relieving its symptoms because without treatment there is an increased risk of developing infertility, endometrial hyperplasia and carcinoma, type 2 diabetes mellitus, metabolic syndrome, and possibly cardiovascular disease (16–18). Available treatment options include oral contraceptive pills (OCP) and metformin (19, 20). Only a
Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 5/27/15 3:28 AM
2 Al-Zubeidi and Klein: PCOS in adolescents
few studies have compared these two treatments in adolescents with varying results (21, 22). We studied 22 patients between the ages of 12 and 18 years, randomized to receive either metformin or OCP for 6 months, and followed for 3 months off treatment. We report changes in body mass index (BMI), free testosterone (FT), menses, and quality of life.
Patients and methods The study population was composed of 34 adolescent girls between the ages 12 and 18 years. They were recruited from the pediatric endocrinology clinic at Rady Children’s Hospital, San Diego, CA, USA. The reason for referral varied and included evaluation for obesity, irregular menses, and hirsutism. Inclusion of patients in the study was based on the NIH criteria for the diagnoses of PCOS in this age group, which includes irregular menses or amenorrhea and elevated free or total testosterone. Irregular menses or amenorrhea was defined as less than or equal to eight menses per year. In addition, other causes of hyperandrogenism were excluded including: adrenal tumors, late congenital adrenal hyperplasia, and prolactinomas. Patients were only enrolled 2 years post-menarche given the potential for menstrual irregularity in normal maturation post-menarche. Exclusion criteria included: current treatment or treatment within the last 3 months with metformin or OCP and personal or family history of blood clotting disorders, breast cancer, stroke, severe migraines with aura, elevated blood pressure, defined as either systolic and/or diastolic BP ≥ 95th percentile measured upon three or more occasions, and smoking defined by more than one pack per day for the past 6 months. The study received approval from the University of California San Diego Institutional Review Board. Informed consent was obtained from a parent or guardian, and assent was obtained from each patient. Each patient was randomly assigned to group 1 or group 2 using concealed assignments from random numbers that were computer generated. Those randomized to group 1 were assigned to receive metformin, and those randomized to group 2 were assigned to receive OCP. Routine counseling about diet and exercise was done in clinic, but no specific exercise or diet prescription was offered. Loestrin (1 mg norethindrone acetate and 30 μg ethinyl estradiol) was chosen for the OCP arm. Based on our clinical experience and practice, it was well tolerated by adolescents, and no side effects were reported in our study. Metformin was prescribed with a gradual increase in dose to a daily dose of 1 g BID. Maximum dose was reached over a 3-week period. In the metformin study group, 30% of the patients enrolled experienced GI side effects which included nausea, stomach upset, and diarrhea; one patient remained on 1500 g for a week until symptoms resolved then returned back to 2000 g daily without any symptoms; another patient required a longer time to reach maximum dose, and the third patient continued to have intermittent diarrhea on the maximum dose. All patients were evaluated at baseline, 3 and 6 months on treatment, and 3 months after discontinuation of treatment. Evaluation included a physical exam, height, weight, BMI, Ferriman-Gallwey scoring for hirsutism, review of menstrual calendar, and the use of
a validated quality of life questionnaire (23). The quality of life questionnaire was composed of two forms: a teen report with questions regarding health/school/activities and a general well being form with questions regarding mood and feelings. Blood sampling was performed for hormone determinations at each visit at Quest Diagnostics Laboratory (San Diego, CA, USA) and included: gonadotropins, SHBG, progesterone, and androgens, including 17-hydroxyprogesterone, androstenedione, total and free FT The total testosterone levels were measured by liquid chromatography tandem mass spectrometry (LC/MS/MS) with an analytical sensitivity: 1.0 ng/dL, analytical specificity: no cross-reactivity with 30 testosterone-related steroid compounds and a reportable range: 1.0 ng/dL–2000 ng/dL. The percent FT was measured by equilibrium dialysis and was calculated based on total and percent FT A fasting blood sample was also obtained for glucose, insulin, and a lipid panel. Homeostatic model assessment (HOMA) method was used to assess beta-cell function and insulin resistance. A urine pregnancy test was done for all patients at baseline. For the purpose of this study, patients were asked to commit to not getting pregnant while in the study and if sexually active were advised to use some form of birth control other than OCPs. All data expressed as mean with SD in parentheses. All patients received monthly phone texts to improve compliance and assess non-adherence to the prescribed regimen. Patients were also asked to bring their medication to every clinic visit for a pill count, and a reminder was sent to them prior to the clinic visit. Once the medication was prescribed, we also contacted the pharmacy to ensure that patients picked up the medication as instructed by the physician.
Data analysis The primary endpoints were the change in FT level and BMI over the 6-month period, on each of the two treatment options, and the study was powered for these endpoints. Sample size was estimated with a desired power of 0.8 and a two-tailed alpha of 0.05, and assuming a mean and SD of the baseline FT 1.1±0.45 from a previous study (24). We assumed that a 50% drop in the FT level from baseline was clinically significant. To demonstrate a 50% change in FT, 26 patients were needed. We recruited 34 adolescent girls to allow for dropouts. Baseline covariates tested were insulin, glucose, HOMA-IR, menses/ month, quality of life, and Ferriman-Gallwey score. A p
Hiba Al-Zubeidi and Karen O. Klein*
Randomized clinical trial evaluating metformin versus oral contraceptive pills in the treatment of adolescents with polycystic ovarian syndrome Abstract
Introduction
Background: Polycystic ovarian syndrome (PCOS) is characterized by irregular menses, elevated androgens, and insulin resistance. Little information is published about the treatment of adolescent PCOS. Objectives: The aim of this study was to evaluate metformin versus oral contraceptive pills (OCP) in treating adolescent PCOS. Twenty-two girls were randomized to either treatment for 6 months. The outcomes variables included body mass index (BMI) and free testosterone (FT). Results: BMI decreased in all patients (metformin p = 0.004, OCP p = 0.045). FT decreased significantly only with OCP. Insulin resistance measures decreased in all patients but did not reach significance. The only significant difference in any of the variables between the two groups was number of menses. BMI and FT remained less than baseline for 3 months off treatment. Conclusions: Metformin and OCP have a positive effect on BMI, which persists after treatment is discontinued. FT decreased with both treatments, but only reached significance with OCP. Keywords: adolescent polycystic ovarian syndrome; hyperandrogenism; irregular menses; metformin; oral contraceptives. DOI 10.1515/jpem-2014-0283 Received July 2, 2014; accepted January 23, 2015
*Corresponding author: Karen O. Klein, MD, Rady Children’s Hospital San Diego, San Diego, CA, USA; Department of Pediatrics Endocrinology, University of California, San Diego, CA, USA, Phone: +858-966-4032, Fax: +858-966-6227, E-mail: [email protected] Hiba Al-Zubeidi: Le Bonheur Children’s Hospital, Memphis, Tennessee, Department of Pediatric Endocrinology, University of Tennessee Health Science Center, Memphis, TN
Polycystic ovarian syndrome (PCOS) is the most common metabolic disorder in women of reproductive age. The estimated prevalence varies depending on the diagnostic criteria used. In adult women, the prevalence in several studies identified PCOS with a prevalence of 4%–12% (1– 3). In some European studies, the prevalence of PCOS has been reported to be 6.5%–8% (4). In adolescents, accurate data about the incidence and prevalence of PCOS is scant with higher incidence associated with obesity (5–8) and in first-degree relatives and patients with a history of premature adrenarche (9, 10). PCOS is primarily characterized by ovulatory dysfunction and hyperandrogenism. Insulin resistance or obesity, both commonly associated with this disorder appears to further amplify the severity of the presentation (11). The pathophysiology of PCOS has not been fully characterized. Many patients have evidence of abnormal luteinizing hormone (LH) secretion in which patients have higher serum concentrations and increased frequency and amplitude of LH pulses. A significant percentage of patients with PCOS display insulin resistance. The combination of insulin resistance and increased LH secretion appears to stimulate ovarian androgen production. In addition, elevated insulin levels inhibit hepatic synthesis of sex hormone binding globulin (SHBG) (11, 12). These changes result in increased bioavailability of free androgens. Excess androgen production in PCOS patients has been shown to cause premature ovarian follicle arrest leading to anovulation and menstrual irregularities (11–15). Thus, the combination of elevated LH, hyperinsulinemia, and ovarian androgen production produces the PCOS phenotype of oligoovulation and hyperandrogenism. Treating PCOS in adolescents is important beyond relieving its symptoms because without treatment there is an increased risk of developing infertility, endometrial hyperplasia and carcinoma, type 2 diabetes mellitus, metabolic syndrome, and possibly cardiovascular disease (16–18). Available treatment options include oral contraceptive pills (OCP) and metformin (19, 20). Only a
Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 5/27/15 3:28 AM
2 Al-Zubeidi and Klein: PCOS in adolescents
few studies have compared these two treatments in adolescents with varying results (21, 22). We studied 22 patients between the ages of 12 and 18 years, randomized to receive either metformin or OCP for 6 months, and followed for 3 months off treatment. We report changes in body mass index (BMI), free testosterone (FT), menses, and quality of life.
Patients and methods The study population was composed of 34 adolescent girls between the ages 12 and 18 years. They were recruited from the pediatric endocrinology clinic at Rady Children’s Hospital, San Diego, CA, USA. The reason for referral varied and included evaluation for obesity, irregular menses, and hirsutism. Inclusion of patients in the study was based on the NIH criteria for the diagnoses of PCOS in this age group, which includes irregular menses or amenorrhea and elevated free or total testosterone. Irregular menses or amenorrhea was defined as less than or equal to eight menses per year. In addition, other causes of hyperandrogenism were excluded including: adrenal tumors, late congenital adrenal hyperplasia, and prolactinomas. Patients were only enrolled 2 years post-menarche given the potential for menstrual irregularity in normal maturation post-menarche. Exclusion criteria included: current treatment or treatment within the last 3 months with metformin or OCP and personal or family history of blood clotting disorders, breast cancer, stroke, severe migraines with aura, elevated blood pressure, defined as either systolic and/or diastolic BP ≥ 95th percentile measured upon three or more occasions, and smoking defined by more than one pack per day for the past 6 months. The study received approval from the University of California San Diego Institutional Review Board. Informed consent was obtained from a parent or guardian, and assent was obtained from each patient. Each patient was randomly assigned to group 1 or group 2 using concealed assignments from random numbers that were computer generated. Those randomized to group 1 were assigned to receive metformin, and those randomized to group 2 were assigned to receive OCP. Routine counseling about diet and exercise was done in clinic, but no specific exercise or diet prescription was offered. Loestrin (1 mg norethindrone acetate and 30 μg ethinyl estradiol) was chosen for the OCP arm. Based on our clinical experience and practice, it was well tolerated by adolescents, and no side effects were reported in our study. Metformin was prescribed with a gradual increase in dose to a daily dose of 1 g BID. Maximum dose was reached over a 3-week period. In the metformin study group, 30% of the patients enrolled experienced GI side effects which included nausea, stomach upset, and diarrhea; one patient remained on 1500 g for a week until symptoms resolved then returned back to 2000 g daily without any symptoms; another patient required a longer time to reach maximum dose, and the third patient continued to have intermittent diarrhea on the maximum dose. All patients were evaluated at baseline, 3 and 6 months on treatment, and 3 months after discontinuation of treatment. Evaluation included a physical exam, height, weight, BMI, Ferriman-Gallwey scoring for hirsutism, review of menstrual calendar, and the use of
a validated quality of life questionnaire (23). The quality of life questionnaire was composed of two forms: a teen report with questions regarding health/school/activities and a general well being form with questions regarding mood and feelings. Blood sampling was performed for hormone determinations at each visit at Quest Diagnostics Laboratory (San Diego, CA, USA) and included: gonadotropins, SHBG, progesterone, and androgens, including 17-hydroxyprogesterone, androstenedione, total and free FT The total testosterone levels were measured by liquid chromatography tandem mass spectrometry (LC/MS/MS) with an analytical sensitivity: 1.0 ng/dL, analytical specificity: no cross-reactivity with 30 testosterone-related steroid compounds and a reportable range: 1.0 ng/dL–2000 ng/dL. The percent FT was measured by equilibrium dialysis and was calculated based on total and percent FT A fasting blood sample was also obtained for glucose, insulin, and a lipid panel. Homeostatic model assessment (HOMA) method was used to assess beta-cell function and insulin resistance. A urine pregnancy test was done for all patients at baseline. For the purpose of this study, patients were asked to commit to not getting pregnant while in the study and if sexually active were advised to use some form of birth control other than OCPs. All data expressed as mean with SD in parentheses. All patients received monthly phone texts to improve compliance and assess non-adherence to the prescribed regimen. Patients were also asked to bring their medication to every clinic visit for a pill count, and a reminder was sent to them prior to the clinic visit. Once the medication was prescribed, we also contacted the pharmacy to ensure that patients picked up the medication as instructed by the physician.
Data analysis The primary endpoints were the change in FT level and BMI over the 6-month period, on each of the two treatment options, and the study was powered for these endpoints. Sample size was estimated with a desired power of 0.8 and a two-tailed alpha of 0.05, and assuming a mean and SD of the baseline FT 1.1±0.45 from a previous study (24). We assumed that a 50% drop in the FT level from baseline was clinically significant. To demonstrate a 50% change in FT, 26 patients were needed. We recruited 34 adolescent girls to allow for dropouts. Baseline covariates tested were insulin, glucose, HOMA-IR, menses/ month, quality of life, and Ferriman-Gallwey score. A p
