{"paper_id":"0e549282-91e7-4b27-8de7-194f9af08fb0","body_text":"Clomiphene citrate (CC) is an agent that has\nbeen used since the 1960s for ovulation induction.\nIn appropriately selected anovulatory women, CC\nsuccessfully induces ovulation in about 70-80% of\ncases; among these women the overall cycle fecundability\nis approximately 15% ( 1 ). CC is generally\nused as the first step in treating early stage\nendometriosis, anovulation that is related to unexplained\ninfertility and borderline male factor infertility\nwith decreased requirements for close monitoring\n( 2 ). CC acts on the central nervous system as\nan anti-estrogen and increases the pulse frequency\nof follicle stimulating hormone (FSH) and luteinizing\nhormone (LH), in order to induce ovulation.\nThis anti-estrogen effect also has negative impacts\non the endometrium and cervical mucus ( 3 ,  4 ).\nFactors that affect pregnancy rates in CC cycles\nhave been reported in previous studies. The ages\nof the women, longer duration times of their infertility\nand decreased ovarian reserves have been described\nas factors that indicate poor prognosis for\npregnancy in CC cycles ( 5 ). The diameter of the\nleading follicle on the day before human chorionic\ngonadotropin (hCG) administration and the endometrial\nthickness (ET) have also been evaluated in\nrelation to the success of CC cycles ( 6 ).\nIn addition, Doppler velocimetry studies have\nbeen conducted to evaluate the changes in blood\nflow in the uterus and ovaries during the normal\nmenstrual cycle ( 7 ,  8 ). Ng et al. ( 9 ) reported their\nfindings on the effects of Doppler velocimetry on\nthe blood supply to the entire endometrium and the\nsub-endometrial region. These authors evaluated\nthe role of endometrial and sub-endometrial vascularity\nin women who underwent frozen-thawed\nembryo transfer (FET) cycles and found that neither\nof these blood flow measures was a good predictor\nof pregnancy in FET cycles. Nakai et al.\n( 10 ) also discussed their findings on uterine artery\nDoppler velocimetry in cycles stimulated by CC.\nTheir study found lower endometrial perfusion.\nThe current study evaluated the effectiveness of\nDoppler velocimetries of the uterine and ovarian\narteries as a predictor of successful pregnancy in\nCC cycles.\n\nThis interventional, cross-sectional study was\nundertaken from May 2013 to June 2013 in the\nDepartment of Obstetrics and Gynecology, Division\nof Infertility and Gynecological Endocrinology\nat Dr. Zekai Tahir Burak Women’s Health\nEducation and Research Hospital. This is a tertiary\nreferral research hospital located in the central region\nof Turkey. It is a government-supported hospital\nwhere most of the health services are offered\nfree of charge.\nThe study was designed according to the Helsinki\nDeclaration ( 11 ) and all patients gave written\ninformed consent. The study was also approved by\nthe Ethics Research Committee of Dr Zekai Tahir\nBurak Women’s Health Education and Research\nHospital (Ankara, Turkey).\nWomen who had had unexplained infertility (primary\nor secondary) for at least one year were included\nin the study. A total of 80 women received\noral CC, 100 mg daily, from day 3 to day 7 of their\nmenstrual cycles. All of the cases received regular\nultrasound monitoring for follicle growth and\nET through transvaginal ultrasonography on day\n12 of their cycles and again every other day until\nthe leading follicle reached 17-23 mm, triggered\nby hCG. Transvaginal Doppler velocimetry waveforms\nwere also obtained from the bilateral uterine\nand ovarian arteries of each patient for analysis.\nThe ultrasound examinations, performed on day 3\nof the menstrual cycle while the patients were in\nthe lithotomy position used color Doppler sonography\nwith a 7.5 MHz pulse endovaginal Doppler\nsystem for blood flow analysis (Aloka Co., Tokyo,\nJapan). The women’s bladders were emptied before\ntheir examinations. The uterine artery was located\nlaterally to the isthmic region of the uterus\nand the ovarian artery was found at the lateral pole\nof the ovary near the infundibulopelvic ligament.\nThe following factors that affected patients’ risk\nlevels were recorded: age, infertility type, duration\nof infertility, gravidy, parity, number of pregnancy\nlosses, number of living children, ET, cycle day 3\nserum FSH, LH and estradiol (E2) levels, uterine\nand ovarian artery Doppler velocimetries, number\nof antral follicules, dominant follicle sizes and\npregnancy. The Doppler velocimetries measured\nwere the right side uterine and ovarian artery pulsatility\nindex (PI) and resistance index (RI) in addition\nto the left side uterine and ovarian artery PI\nand RI.\nThe cases were divided into two groups according\nto whether patients achieved pregnancy or not.\nAt the end of the study, a total of 6 (7.5%) patients\nwere pregnant. Pregnancy was determined by positive\nβ-hCG and a visible intrauterine gestational\nsac.\nThe primary outcome measure was a clinical\npregnancy. Continuous variables were not normally\ndistributed and recorded as median (interquartile\nrange) unless otherwise indicated. The normal\ndistribution of the variables was analyzed by the\nKolmogorov-Smirnov test. Statistical comparison\nwas carried out by Chi-square (χ 2 ), Mann-Whitney\nand independent sample t tests where appropriate.\nThe sample size was determined according to the\nresults of the central limit theorem ( 12 ). Statistical\nanalysis was performed using the Statistical\nProgram for Social Sciences (SPSS, Version 15.0,\nChicago, IL, USA). The two-tailed value of p<0.05\nwas considered statistically significant.\n\nThe demographic and clinical characteristics of\nthe cases are shown in  table 1 . The study included\n80 patients who had had unexplained infertility for\nat least one year. The pregnancy rate was 7.5%.\nThe mean age of the cases was 26.83±4.95 years\nfor the group that achieved pregnancy and 27.45\n±5.53 years for the group that did not (p=0.789).\nThere were 54 (67.5%) cases of primary infertility.\nThe median (min-max) gravidy and parity of the\ncases were 0.41 (0-3) and 0.23 (0-2), respectively.\nThe infertility type (primary or secondary) showed\nno statistically significant differences between the\ngroups in terms of pregnancy rate (p=0.640). The\nmean duration of infertility was 2.58±0.80 years for\nthe group that achieved pregnancy and 3.93±2.34\nyears for the group that did not. These values showed\nstatistically significant differences between the\ngroups (p=0.007). The ET on day 3 of the cycle\nwas 1.83±0.98 mm in the group that achieved\npregnancy and 2.37±1.02 mm in group that did\nnot, with no statistically significant differences\n(p=0.241).\nThe differences in demographic and clinical characteristics among the pregnant and non-pregnant groups\nCI; Confidence interval, *; P values calculated by χ2 test, FSH; Follicle stimulating hormone, LH; Luteinizing hormone, E2; Estradiol and\nET; Endometrial thickness.\nThe differences between the basal blood hormone\nlevels of the FSH, LH and E2 values were\nalso not statistically significant between the\ngroups (p>0.05). However, the durations of infertility\nof the two groups showed statistically\nsignificant differences (p<0.007). The basal\nfollicle numbers were 6.66±3.72 for the right\novary and 6.75±3.15 for the left ovary in the\ngroup that achieved pregnancy and 6.33±4.08\n(right ovary) and 6.67±3.17 (left ovary) for the\ngroup that did not. The mean diameters of the\nleading follicle on the day that hCG was administered\nfor the group that achieved pregnancy\nwas 16.50±6.44 mm and for the group that did\nnot achieve pregnancy it was 15.16±4.51 mm,\nfor the right ovary. For the left ovary, this value\nwas 15.16±7.30 mm in the group that achieved\npregnancy versus 14.77±4.82 mm in the group\nthat did not achieve pregnancy (p>0.05).\nThe measurement of Doppler velocimetry on\nday 3 of the cycle was as follows: the right side\nuterine artery mean (min-max) was PI: 3.33 ±\n2.40, RI: 1.14±0.59, the right side ovarian artery\nwas PI: 2.30±1.97, RI: 1.11±0.87; the left\nside uterine artery was PI: 3.11±1.91, RI: 1.21\n±0.64 and the left side ovarian artery was PI:\n3.29±2.31, RI: 1.10±0.72.\nTable 2  shows the Doppler velocimetry values\nof the two groups. There were no statistically\nsignificant differences between the groups\n(p>0.05).\nDoppler velocimetries of uterine and ovarian arteries among the pregnant and non-pregnant groups\nCI; Confidence interval, PI; Pulsatility index and RI; Resistance index.\n\nIn this study we examined 80 women who had\nunexplained infertility for at least one year with\nthe intent to evaluate the uterine and ovarian artery\nDoppler velocimetries as predictors of a successfully\nachieved pregnancy. The patients received\noral CC, 100 mg daily, from day 3 to day 7 of their\nmenstrual cycles. At the end of the study, 6 (7.5%)\nof the patients had achieved pregnancy. We divided\nthe cases into two groups based on whether the patient\nhad achieved pregnancy or not and found that\nthe demographic and clinical parameters showed\nno statistically significant differences between\nthe groups. However, the differences between the\ngroups in terms of the durations of infertility were\nstatistically significant. The Doppler velocimetry\nvalues also showed no statistically significant differences\nbetween the groups.\nDoppler velocimetry of the uterine, spiral and\novarian arteries has been previously investigated\nin different types of cases, various phases of\nthe menstrual cycle, ovulation induction and in\nearly pregnancy. First, Kupesic and Kurjak ( 13 )\nreported that blood flow in the uterine, spiral\nand ovarian arteries has a predictive value in\nendometrial receptivity. Bassil et al. ( 14 ) have\nalso demonstrated that the RI values of the\novarian artery are a good indicator of ovarian\ninhibition and may be used to assess the optimal\ntiming for the beginning of human menopausal\ngonadotrophin. In addition, Dickey et al. ( 15 )\nhave found impedance of the spiral artery to be\na predictive parameter in the early development\nof the embryo. Based on these findings, we decided\nto conduct a study to evaluate the Doppler\nvelocimetry in CC cycles.\nNakai et al. ( 10 ) studied the Doppler velocimetry\nvalues for spontaneous and stimulated menstrual\ncycles in women with unexplained infertility and\nfound that the uterine blood flow was higher in\nspontaneous cycles than in cycles stimulated with\nCC.\nIn addition, Ragni et al. ( 16 ) evaluated 318 cases\nthat received mild controlled ovarian stimulation\n(COS) and intrauterine insemination (IUI). They\nassessed the vascularity of the dominant follicle\nby Doppler ultrasound. These authors reported\nthat Doppler velocimetry of follicular vascularity\ndid not predict the chances for pregnancy in COS\nand IUI cycles. The findings of the current study\nwere similar to this study; we have also believed\nthat Doppler velocimetry of the uterine and ovarian\narteries are not good predictors for achieving\npregnancy.\nIn a previous study, Ng et al. ( 17 ) reported that\nthe Doppler velocimetry values of uterine and\novarian arteries showed no differences between\nthe early follicular phase and an ensuing CC challenge\ntest.\nBaruah et al. ( 18 ) designed a study with COS patients\nusing letrozole or CC and studied the Doppler\nvelocimetry of the spiral arteries. The study found\nthat the letrozole group showed significantly lower\nimpedance than the CC group and determined\nthat the Doppler velocimetry of spiral arteries was\na supportive tool for evaluating endometrial response\nin the treatment of anovulatory polycystic\novary syndrome patients with infertility.\n\nWe believe that Doppler velocimetries of the\nuterine and ovarian arteries are not prognostic factors\nfor pregnancy in CC cycles.","source_license":"CC-BY-4.0","license_restricted":false}