To evaluate the efficacy and safety of letrozole on ovulation induction and pregnancy in infertility patients with polycystic ovary syndrome and to analyze the insulin resistance in these patients.
Journal of military pharmaco-medicine no8-2019 EFFECT OF INTRAUTERINE INSEMINATION ON WOMEN WITH POLYCYSTIC OVARY SYNDROME STIMULATED BY LETROZOLE Nguyen Thanh Tung1; Lam Thi Mai Ngoc2; Quan Hoang Lam1 SUMMARY Objectives: To evaluate the efficacy and safety of letrozole on ovulation induction and pregnancy in infertility patients with polycystic ovary syndrome and to analyze the insulin resistance in these patients Subjects and methods: Progressive description study with comparison The study included 80 infertility women divided into groups: 40 women with polycystic ovary syndrome (the study group) and 40 women without polycystic ovary syndrome (the control group) The both groups used letrozole for ovulation induction from cycle day When a development follicle size reaches at least ≥ 18 mm triggered by hCG 5,000 IU, intrauterine insemination was performed after 36h Results: On hCG trigger day revealed no differences in the dominant follicle and endometrial thickness between the study group and the control group (1.16 ± 0.37 folicles; 8.78 ± 1.08 mm and 1.30 ± 0.46 follicles; 9.08 ± 1.16 mm, respectively) Number of day until the follicle mature appears to be higher in the study group (13.08 ± 2.38 days) compared to the control group (11.93 ± 1.35 days), p < 0.05 The pregnancy rate was 22.5% of the both groups The average insulin of the study group (10.85 ± 5.84 µUI/mL) and their average HOMA-IR (2.42 ± 1.34) were higher than the control group (7.44 ± 2.84 µUI/mL and 1.57 ± 0.68), p < 0.05 The QUICKI of the study group (0.31 ± 0.03) was shorter than the control group (0.36 ± 0.02), p < 0.05 Conclusion: Letrozole was used to stimulate the ovaries of the infertile women with polycystic ovary syndrome combined with intrauterine insemination is the effective treatment These patients had the high risk of insulin resistance * Keywords: Polycystic ovary syndrome; Aromatase inhibitor; Letrozole; Insulin resistance; Intrauterine insemination INTRODUCTION Polycystic ovary syndrome (PCOS) is the most common cause of infertility that affects - 10% of women in reproductive age [2] Infertility due to anovulation affects 75% of women with PCOS [3] The clinical characteristics of women with PCOS are oligo-anovulation; hyperandrogenism; polycystic ovaries on ultrasound examination [4] There are some methods which used to treat the women with PCOS, the ovarian stimulation combined with intrauterine insemination (IUI) is widely applied Recently, aromatase inhibitor is prevalently used in order to stimulate the ovaries in infertility treatment Vietnam Military Medical University Phutho Obstetrics and Pediatrics Center Corresponding author: Nguyen Thanh Tung (tung_ttcnp@yahoo.com) Date received: 17/09/2019 Date accepted: 10/10/2019 154 Journal of military pharmaco-medicine no8-2019 The mechanism of aromatase inhibitors (AIs) is to exert an ovulation-inducing effect by inhibiting the aromatase, and ubiquitous (but mostly found in the granulosa cells, fat tissue, and placenta) It is responsible for the androgen-to-estrogen conversion, that is the rate-limiting step in estrogen synthesis AIs administration induces an acute hypoestrogenic state that releases the hypothalamic-pituitary axis from estrogenic negative feedback, which in turn increases FSH secretion and ovarian follicle development AIs increase serum LH, androstenedione and testosterone levels, that support the follicle growth [5] * Selection criteria: Patients under 35 years old, normal husband's semen analysis according to WHO (2010) criteria, normal fallopian tubes Letrozole is the third-generation AIs and has the shorter half-life Letrozole does not deplete estrogen receptors and is devoid of any anti-estrogenic peripheral actions; therefore, it has no effect make endometrial thinner According to Rotterdam (2003) criteria when there are at least 2/3 of the following criteria [3]: Since 1990, PCOS was recognized as the metabolism disorder with insulin resistance and insulin increasing in the blood That makes the ovarian dysfunction - The presence of 12 or more antral follicles in an ovary or ovarian volume of more than 10 mL on ultrasound examination Antral follicles are defined as measuring between and mm in diameter Therefore, we performed this study in order: To evaluate the efficacy and safety of letrozole on ovarian stimulation and pregnancy in the infertility patients with PCOS In addition to evaluate the insulin resistance of those patients SUBJECTS AND METHODS Subjects 80 patients diagnosed with infertility at the Military Institute of Clinical Embryology and Histology from September 2018 to May 2019 * Exclusion criteria: Asthenozoospermia, bilateral tubal occlusion, uterine malformation, uterine polyps or fibroids 80 infertility patients were divided into two groups: 40 patients with PCOS (study group), 40 patients without PCOS (control group) Methods * Research design: Descriptive, prospective, comparative study * Diagnosis of PCOS: - Oligoovulation or anovulation - Hyperandrogenism (biochemical or clinical) * Ovarian stimulation and IUI technique: Both groups of patients were stimulated to ovaries with letrozole (femara) 2.5 mg x 10 tablets, taken capsules per day, starting from day to day of their menstrual cycle Ultrasonography was performed on cycle day 9, and follicular number, follicular size, and endometrial thickness If there is no dominant follicle (less than 12 mm in diameter), ultrasonography after - days If the dominant follicle 155 Journal of military pharmaco-medicine no8-2019 (12 mm or more) appoints again after days If the follow-up time is longer than 20 days and there is no dominant follicle, then the cycle will be considered a failure and cancel When the follicle reaches 18 mm in diameter, it causes ovulation with hCG 5,000 UI intramuscularly * Research criteria: The ratio of mature follicles and number of days of follicle reached ≥ 18 mm in diameter; endometrial thickness, clinical pregnancy outcome The patient's sperm was collected on the day of IUI, semen samples were prepared by swim up or density gradient centrifugation The volume of sperm used in IUI was 0.3 mL IUI was performed on all patients 36h after hCG injection Data were entered and processed using medical statistical methods, using SPSS 16.0 software Calculating the mean and standard deviation for variables and p < 0.05 is considered to be statistically significant Assess insulin resistance based on HOMA-IR and QUICKI index RESULTS AND DISCUSSION Evaluate the effectiveness of ovarian stimulation letrozole in patients with PCOS PCOS is one of the most common causes of infertility in women The treatment for inducing ovulation by various methods Table 1: Characteristics of groups Groups Study group Control group p value Average age 26.98 ± 3.63 28.52 ± 3.49 > 0.05 Height (cm) 153.98 ± 3.66 153.68 ± 3.40 > 0.05 Weight (kg) 52.22 ± 5.59 49.95 ± 3.48 < 0.05 BMI 22.01 ± 2.17 21.11 ± 1.24 < 0.05 Characteristics Table showed that the age of infertility women with PCOS was quite young, the average age was 26.98 ± 3.63 years old, mostly primary infertility (72.5%) Obesity is one of the common factors mentioned in women with PCOS, in our study there was a significant difference between infertility group with PCOS and average BMI of 22.01 ± 2.17 higher than the group without PCOS with the average BMI was 21.11 ± 1.24 Our findings were also consistent with Le Minh Tam's study of BMI in patients with PCOS of 20.9 ± 2.9 [1] 156 Journal of military pharmaco-medicine no8-2019 Table 2: Characterization of reproductive endocrinology Groups Study group Control group p value FSH (mIU/mL) 6.67 ± 2.15 8.33 ± 2.65 > 0.05 LH (mIU/mL) 10.76 ± 6.63 7.43 ± 3.62 < 0.05 E2 (pg/mL) 74.97 ± 57.07 66.58 ± 45.24 > 0.05 9.68 ± 3.57 3.49 ± 1.75 < 0.05 Lab tests AMH (ng/mL) LH, AMH concentrations between the two groups differed statistically with p < 0.05 Table 3: The effects of letrozole on ovarian stimulation Groups Study group Control group p value Average follicles number 1.16 ± 0.37 1.30 ± 0.46 > 0.05 Average follicles diameter (mm) 21.43 ± 2.18 20.98 ± 2.25 > 0.05 Endometrial thickness (mm) 8.78 ± 1.08 9.08 ± 1.16 > 0.05 Ovarian stimulation days 13.08 ± 2.38 11.93 ± 1.35 < 0.05 Outcome On the physiology of oocyte, from day to of menstrual cycles take place the selection and then the superiority of the largest follicle when the size is from 12 mm The average number of ovarian stimulation days in the study group was (13.08 ± 2.38 days) more than the control group (11.93 ± 1.35 days), this difference was statistically significant Another important feature when evaluating the effectiveness of ovarian stimulation is the endometrial thickness as the matures oocyte because this is a prognostic factor for success in the treatment cycle, when using letrozole, the ability to inhibit aromatase, it only takes place for a short time, does not affect the peripheral tissue, so it can limit the adverse effects such as making the endometrial thinner or reducing cervical mucus The endometrial thickness of the study group was 8.78 ± 1.08 mm compared to the control group which was equivalent to 9.08 ± 1.16 mm Number of follicles reached size ≥ 18 mm after stimulation with letrozole in the study group was 1.16 ± 0.37, so close to the natural cycle will avoid the risk of multiple pregnancies Some domestic and foreign authors shared this view Kallol Kumar Roy (2012) found that the number of oocyte in diameter ≥ 18 mm in the letrozole group was 1.86 ± 0.26 follicles [6] Atay et al (2006) reported the number of mature oocytes of letrozole group was 1.2 ± 0.41 follicles [7] 157 Journal of military pharmaco-medicine no8-2019 Table 4: The clinical pregnancy outcome No pregnant Biochemical pregnancy Clinical pregnancy Groups n % n % n % Study group 30 75 2.5 22.5 Control group 31 77.5 0 22.5 Outcome p value > 0.05 A total of 80 patients in the two groups, 18 patients were clinically pregnant, accounting for 23.4% The pregnancy rate between study group and control group was not different with p > 0.05 This result was similar to Sedigheh Dehbashi et al’ study (2015) using letrozole to stimulate the ovaries in patients with PCOS was 26% [8] Atay et al (2006) was 21.6% [7] Polycystic ovarian syndrome and insulin resistance Insulin resistance syndrome is a metabolic disorder that combines insulin resistance with symptoms of obesity, dyslipidemia, hypertension, fasting blood glucose disorders or diabetes There are many methods for assessing insulin resistance, in our study using HOMAR-IR and QUICKI Table 5: Assessment of insulin resistance Group Study group Control group p value Insulin (µUI/mL) 10.85 ± 5.84 7.44 ± 2.84 < 0.05 Glucose (mmol/L) 4.97 ± 0.45 4.71 ± 0.47 < 0.05 HOMA-IR index 2.42 ± 1.34 1.57 ± 0.68 < 0.05 Lab tests Upper quartile QUICKI index 2.016 0.31 ± 0.03 Lower quartile 0.36 ± 0.02 < 0.05 0.3425 HOMA-IR > 2,016 57.5 25 < 0.05 QUICKI < 0,3425 57.5 25 < 0.05 The average concentration of fasting blood insulin test of the study group was 10.85 ± 5.85 µUI, which was statistically higher than the control group of 7.44 ± 2.84 µUI (p < 0.05) In our study, the HOMA-IR of patients with PCOS was (2.42 ± 1.34) higher than the control group (1.57 ± 0.68) with statistical significance with p < 0.05 Our finding was similar to that of Ta Chin Lin (2006) [9] The QUICKI of the patients with PCOS (0.31 ± 0.03) was lower than the control group (0.36 ± 0.02) with statistical significance with p < 0.05 Thus, when only the higher HOMA-IR, the lower QUICKI, the worse insulin resistance will be 158 Journal of military pharmaco-medicine no8-2019 CONCLUSION - Letrozole stimulated the ovaries in women with PCOS in combination with the method of pumping sperm into the uterus to be an effective treatment - Patients with PCOS had the high rick of insulin resistance ovary syndrome Fertility and Sterility 2004, 81, pp.19-25 Casper R.F, Mitwally M.F Aromatase inhibitors for ovulation induction J Clin Endocrinol Metab 2006, 91 (3), pp.760-771 Le Minh Tam, Le Viet Hung, Nguyen Thi Kallol Kumar Roy et al A prospective randomized trial comparing the efficacy of letrozole and clomiphene citrate in induction of ovulation in polycystic ovarian syndrome Journal of Human Reproductive Sciences, 2012, (1), p.20 Phuong Le et al Metabolic disorder in infertility patients with polycystic ovarian syndrome Medical and Pharmaceutical Journal Hue University of Medical and Pharmacy 2017, No 3, 6/2017 (7), pp.7-13 Atay V, Cam C, Muhcu M, Karateke A Comparision of letrozole and clomiphen citrate in women with polycystic ovaries undergoing ovarian stimulation J Med Res 2006, 34 (1), pp.73-66 Asuncion M, Calvo R.M, San Millan J.L, Sancho J, Avila S, Escobar Morreale H.F A prospective study of the prevalence of the polycystic ovary syndrome in unselected causasian women from Spain J Chin Endocrinol Metab 2000, 86, pp.2434-2438 Sedigheh Dehbashi, Sara Dehbashi, Talieh Kazerooni et al Comparison of the effects of letrozole and clomiphene citrate on ovulation and pregnancy rate in patients with polycystic ovary syndrome Iranian Journal of Medical Sciences 2009, 34 (1), pp.23-28 Patel S.M, Nestler J.F Fertility in polycystic ovary syndrome Endocrinol Metab Clin North Am 2006, 35 (1), pp.137-155 Ta-Chin Lin, Jui-Mei Yen, Kum-Bing Gong et al Abnormal glucose tolerance and insulin resistance in polycystic ovary syndrome amongst the Taiwanese population, not correlated with insulin receptor substrate-1 Gly972Arg/Ala513Pro polymorphism BMC Med Genet 2006, 7, p.36 REFERENCES The Rotterdam ESHRE/ASRM sponsored PCOS consensus workshop group Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic 159 ... Kazerooni et al Comparison of the effects of letrozole and clomiphene citrate on ovulation and pregnancy rate in patients with polycystic ovary syndrome Iranian Journal of Medical Sciences 2009,... Journal of military pharmaco-medicine no8-2019 CONCLUSION - Letrozole stimulated the ovaries in women with PCOS in combination with the method of pumping sperm into the uterus to be an effective... stimulation letrozole in patients with PCOS PCOS is one of the most common causes of infertility in women The treatment for inducing ovulation by various methods Table 1: Characteristics of groups