Tuesday, 25 July 2017

Re: Decreases in Anti-mullerian Hormone Levels, a Contributing Factor in Polycystic Ovary Syndrome, Seen after Treatment with Metformin and with the Herbal Medicine DLBS3233; Adverse Effects Reported with the Metformin Therapy

  • Pride-of-India (Lagerstroemia speciosa, Lythraceae)
  • Indonesian Cinnamon (Cinnamomum burmannii, Lauraceae)
  • Metformin
  • Polycystic Ovary Syndrome
Date: 07-14-2017HC# 061731-572

Wiweko B, Susanto CA. The effect of metformin and cinnamon on serum anti-Mullerian hormone in women having PCOS: a double-blind, randomized, controlled trial. J Hum Reprod Sci. 2017;10(1):31-36.

Polycystic ovary syndrome (PCOS) is a condition that affects 15-20% of females of childbearing age worldwide. PCOS is diagnosed when a patient has 2 of the following symptoms as defined by the Rotterdam criteria: oligo- and/or anovulation (OA), hyperandrogenism (HA), or polycystic ovaries (PCO) on ultrasound examination, once other potential morbidities are ruled out. Contributing factors include insulin resistance, seen in 50-70% of females with PCOS, and elevated anti-Mullerian hormone (AMH) levels. Metformin has remained the pharmaceutical agent of choice for patients with PCOS, although research shows pioglitazone provides superior outcomes. However, metformin often produces uncomfortable gastrointestinal side effects, including diarrhea, nausea, and vomiting. The insulin-sensitizing agent metformin is used to manage insulin resistance; however, its effect on AMH levels is unclear. Used in Indonesia, home to these authors, the herbal medicine DLBS3233 (Dexa Medica; Tangarang, Indonesia) has shown beneficial effects on insulin resistance. The product is a standardized extract combination of pride-of-India (Lagerstroemia speciosa, Lythraceae) and Indonesian cinnamon (Cinnamomum burmannii, Lauraceae). The authors conducted a double-blind, randomized, controlled trial to investigate the effects of metformin and DLB3233 on serum AMH levels.
The trial took place between March 2013 and June 2015 in Indonesia at the Yasmin Clinic at RSCM Kencana Hospital in Jakarta and at Hasan Sadikin Hospital in Bandung. Included in the study were women aged between 18 and 40 years who visited the clinic or hospital, were diagnosed with PCOS, and had homeostatic model assessment-insulin resistance (HOMA-IR) levels of 2.0 or higher, indicating insulin resistance. Women who were pregnant, breastfeeding, consumer insulin sensitizing agents or oral contraceptive pills, had Cushing syndrome, late onset congenital adrenal hyperplasia, androgen-secreting tumors, uncontrolled thyroid disease, hyperprolactinemia, or other chronic conditions that might potentially alter the study results were excluded.
Fifty-one patients were randomly assigned to receive 2 metformin (750 mg) tablets and 1 placebo (not described) tablet daily or 1 DLBS3233 (100 mg) tablet and 2 placebo tablets daily for 6 months. Each patient underwent monthly physical examinations. At baseline and after 6 months of treatment, or immediately after a patient was confirmed to be pregnant, blood was drawn to measure AMH and the kidney and liver health markers urea, creatinine, alanine aminotransferase, and aspartate aminotransferase. Adverse effects, menstrual patterns, lifestyle habits, and physical conditions were recorded. Of the 13 patients who did not complete the study, 9 were lost to follow-up, 1 moved to another city, and 3 dropped out because the study was too long for them. The final analysis included 20 patients in the metformin group and 18 in the DLBS3233 group.
No significant between-group differences were seen at baseline. The mean age of the metformin group was 28.25 ± 3.99 years, and in the DLBS3233 group, it was 29.56 ± 3.96 years. In both groups, the most common type of PCOS was phenotype A, indicating the presence of OA, HA, and PCO. Most patients (60% in the metformin group and 88.9% in the DLBS3233 group) were obese. High serum AMH levels were observed in both groups at baseline, with values of 9.30 (+ 5.06) ng/mL in the metformin group and 11.27 (+ 6.47) ng/mL in the DLBS3233 group.
The authors report that after 6 months, the decrease (1.83 (+ 2.43)ng/mL) in AMH level was higher in the metformin group than in the DLBS3233 group, which reported a nonsignificant decrease of 1.15 (+ 2.60) ng/mL (P=0.003). Nausea was reported by 35% of patients in the metformin group; subjects in the DLBS3233 group experienced minimal side effects overall (P = 0.01) and no nausea (P=0.006). Other adverse effects reported in the metformin group included diarrhea, vomiting, headache, and flu-like symptoms. Minimal adverse effects were reported in the DLBS3233 group, resulting in a significant overall between-group difference in the occurrence of adverse effects (P=0.01). Of the 38 subjects in the study, 7 subjects conceived naturally, 5 in the metformin group and 2 in the DLBS3233 group conceived naturally during the study. Upon confirmation of pregnancy, AMH levels were measured and the study treatment was discontinued. In the DLBS3233 group only, a significant decrease was observed in body mass index (BMI) (P=0.017). No significant change in BMI was observed in the subjects who received metformin.
How insulin-sensitizing agents such as metformin decrease AMH levels is unclear, say the authors. In earlier studies, investigators report that metformin therapy improved insulin resistance and polycystic ovarian morphology1 and led to a decrease in AMH levels, follicle number, and ovarian volume2 in patients with PCOS. Specifically, previous research involving PCOS shows that high levels of AMH desensitize follicles to follicle-stimulation hormone (FSH), potentially arresting folliculogenesis. Conversely, suppressing AMH often restores the response of follicles to FSH.
The authors conclude that "both metformin and DLBS3233 could decrease the serum level of AMH," pointing out that "DLBS3233 showed fewer side effects compared to metformin." Limitations of this study include the small number of patients enrolled in the study, the high dropout rate of 25%, and the lack of an investigation of the mechanism of action of DLBS3233 in reducing AMH levels.
Shari Henson

1Bayrak A, Terbell H, Urwitz-Lane R, Mor E, Stanczyk FZ, Paulson RJ. Acute effects of metformin therapy include improvement of insulin resistance and ovarian morphology. Fertil Steril. 2007;87(4):870-875.
2Piltonen T, Morin-Papunen L, Koivunen R, Perheentupa A, Ruokonen A, Tapanainen JS. Serum anti-Mullerian hormone levels remain high until late reproductive age and decrease during metformin therapy in women with polycystic ovary syndrome. Hum Reprod. 2005;20(7):1820-1826.