Uterus & Ovary 2015; 2: e904. doi: /uo.904; 2015 by Ahmed M Maged, et al.

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1 RESEARCH ARTICLE Phytoestrogens as an alternative to estradiol in reversing the antiestrogenic effect of clomid on endometrium in ovulation induction in cases of polycystic ovarian syndrome (PCOS) Ahmed M Maged 1, Wessam S Deeb 2 1 Obstetrics and gynecology department, Cairo University 2 Obstetrics and gynecology department, Fayoum University Correspondence: Ahmed Mohamed Maged Mohamed prof.ahmedmaged@gmail.com Received: July 10, 2015 Published online: July 28, 2015 Objective: To study the effect of phytoestrogens as an alternative to estradiol in reversing the antiestrogenic effect of clomid on endometrium in ovulation induction in cases of PCOS. Methods: Prospective study conducted on 150 women with PCOS were randomly divided using automated web based randomization system into 3 groups: group I included 50 women received CC only50 mg orally every 8 hours started from cycle day 3 for 5 days, group II included 50 women received estradiol from cycle day 7 to day 11 in addition to CC and group III included 50 women received phytoestrogen (20mg of cimifuga racemosa from day 1to12) in addition to CC. Results: There was a statistically significant difference between group I and the other two groups regarding occurrence of ovulation (82 vs.100 and 100 % respectively) A statistically significant difference was found between the three study groups regarding endometrial thickness (5.5±1.07 vs ±1.75 and 10.1±1.87 respectively). Also a significant difference was found between group I and the other two groups regarding pregnancy rate (18 vs.34 and 26 % respectively). Conclusion: Adding phytoestrogens to CC as an alternative to estradiol in PCOS women have increased the count of dominant follicles and improved endometrial thickness and pattern with improvement of both ovulation and pregnancy rates. Keywords: phytoestrogens; estradiol; clomid; ovulation induction; PCOS To cite this article: Ahmed M Maged, et al. Phytoestrogens as an alternative to estradiol in reversing the antiestrogenic effect of clomid on endometrium in ovulation induction in cases of polycystic ovarian syndrome (PCOS). Uterus Ovary 2015; 2: e904. doi: /uo.904. Introduction Polycystic ovary syndrome (PCOS) is a heterogeneous condition associated with menstrual irregularities and hyperandrogenic state. It is diagnosed with the presence of at least two of the following criteria: oligo or anovulation, elevated androgens or clinical androgen excess and ultrasonographic picture of polycystic ovaries [1]. The prevalence of PCOS differs with different ethnic group and geographic area. It occurs in approximately 4% or 18% of females on reproductive-aged worldwide [2]. So it is one of the commonest endocrinological disorders in females and the commonest cause of ovulatory dysfunction. Practically, 75% of PCOS women have infertility caused by ovulatory dysfunction [3] and 50% of them have recurrent pregnancy loss [4]. PCOS is diagnosed in 74%of females complaining of hirsutism [1]. Clomiphene citrate (CC) is an estrogen analog that was first used in induction of ovulation in 1961 and clinically approved in the United States in Clomiphene exerts both estrogen agonist and antagonist effects [5]. CC binds with hypothalamic estrogen receptors exerting antiestrogenic Page 1 of 5

2 effect. The block of receptors stimulates the release of gonadotropin-releasing hormone (GnRH) which stimulates the anterior pituitary gland to secrete gonadotropin. CC is most commonly used as a first-line treatment of infertility [6]. CC is successful in ovulation induction in 80% of cases, however the cumulative pregnancy rates reaches 30-40% only after its use for a few cycles. The discrepancy between ovulation and cumulative pregnancy rates is due to the antiestrogenic effects of CC on both endometrial lining and the quality of cervical mucus [5]. The endometrial thickness is significantly thinner in women under CC treatment than those not under such treatment [7, 8]. The aim of our study is to assess the effectiveness and safety of phytoestrogens as an alternative to estradiol in reversing the antiestrogenic effect of clomid on endometrium in ovulation induction in cases of PCOS. Material and methods This prospective randomized study was conducted at Kasr El Aini Hospital, Cairo University and Fayoum university hospital Egypt, in the period from January 2013 to April After approval of local ethical committee, informed written consent was obtained from 150 women attending the infertility outpatient clinic. All participants had the diagnosis of polycystic ovarian syndrome (PCOS) based on presence of a minimum of two criteria of the following: ovulatory dysfunction; evidence of hyperandrogenic state either clinically clinical (e.g., hirsutism and acne) and/or biochemical measurements; or ultrasonographic picture of polycystic ovaries and/or multiple discrete follicles in diameter in one ovary. Women with both 1ry and 2ry infertility were included. All women were between 20 and 37 years old [9]. Exclusion criteria included women with endocrinological abnormalities as thyroid dysfunction or abnormal prolactin levels, those with hypothalamic or pituitary dysfunctions evaluated by low gonadotropin level, other causes of infertility as tubal factor evaluated by HSG or laparoscopy, abnormal uterine cavity evaluated by sonohystrography or hysteroscopy and male factor evaluated by semen analysis. Women with ovarian cysts were also excluded from the study. The patients were subjected to history taking, including age, duration and type of infertility and medical history. Full examination including general and abdominal and vaginal examination was done followed by ultrasound evaluation for exclusion of ovarian cysts. Basal day 3 hormonal evaluation for FSH, LH and E2 in a natural cycle was done. E2, FSH, LH and prolactin levels were determined using Immulite system (Siemens Healthcare diagnostics, UK).The intra- and inter-assay coefficients of variation were 15% and 16% for E2, 4.8% and 26% for LH. FSH analytical sensitivity was 0.1 miu/ml. Patients were randomized at the beginning of each cycle by sealed opaque envelopes containing random generated numbers into three groups. All patients received clomiphene citrate (clomid global Napi, 6 th October Egypt) 50 mg orally every 8 hours started from cycle day 3 for 5 days. Group 1 (50 patients) received no further treatment. Group 2 (50 patients) received estradiol (cycloprogynova white tablets schering, Germany) from cycle day 7 to day 11. Group 3 (50 patients) received phytoestrogen (Klimadynon( ), Bionorica, Neumarkt i.d.obf., Germany) (20mg of cimifuga racemosa from day 1to12) A transvaginal ultrasonography (TVS) Toshiba femio 5 (Toshiba Medical Solutions Inc., Ultrasound Division, Japan) equipped with a 6.5 MHz transvaginal transducer was done on alternate days starting from cycle day 9 till ovulation to determine the follicular number, size, endometrial thickness and pattern and evidence of follicular rupture. The primary outcome parameter evaluated was clinical pregnancy (defined as the presence of gestational sac containing fetal hearts on ultrasound scan). Other parameters included occurrence and day of ovulation, endometrial thickness and pattern, number and size of follicles. Data were statistically described in terms of mean ± standard deviation (± SD), median and range, or frequencies (number of cases) and percentages when appropriate. The Mann-Whitney U-test using the Bonferroni correction, Fisher s test, and Kruskal Wallis H-test were employed as appropriate. P values less than 0.05 was considered statistically significant. All statistical calculations were done using computer programs SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) version 15 for Microsoft Windows. Results Our study included 150 women with PCOS were randomly divided using automated web based randomization system into 3 groups: group I included 50 women received CC only50 mg orally every 8 hours started from cycle day 3 for 5 days, group II included 50 women received estradiol from cycle day 7 to day 11 in addition to CC and group III Page 2 of 5

3 Table 1. Characteristics among study groups GI (CC) GII (CC+ E2) GIII (CC+ P value Phyto) I*II I*III II*III Age (years)* BMI (kg/m 2 ) 28.3 ± ± ± Duration of infertility (years)* 1.79± ± ± Type of infertility** Primary 27( ( ( Secondary 23( ( (58.0 Menstrual pattern ** Regular 28(56.% 24(48% 34(68% Oligo 17(34% 23(46% 13(26% Ameno 5(10% 3(6% 3(6% LH/FSH ratio* 1.07± ± ± US picture of PCO** Yes 100% 100% 100% No * Data are presented as mean ± SD. ** Data are presented as number (percent). Table 2. Outcome parameters among study groups GI (CC) GII (CC+ GIII (CC+ P value E2) Phyto) I*II I*III II*III Average number of follicles Follicles < 14 mm* 2.04± ± ± Average number of follicles Follicles mm* 2± ± ± Average number of follicles Follicles > 18 mm* 1.42± ± ± Stimulation days 10.08± ± ± Ovulation** Yes 41(82% 50(100% 50(100% No 9(18% 0 0 Endometrial thickness *(mm) 5.5± ± ± Endometrial pattern Triphasic 0 46(92% 40(80% Poor Thin 50(100% 0 10(20% Pregnancy rate ** Yes 9(18% 17(34% 18(36% No 41(82% 33(66% 32(64% * Data are presented as mean ± SD. ** Data are presented as number (percent). included 50 women received phytoestrogen (20mg of cimifuga racemosa from day 1to12) in addition to CC. There was no significant difference between the three study groups regarding age, BMI, duration of infertility, type of infertility, menstrual pattern mean LH/FSH ratio and those with ultrasonographic picture of PCOS (table 1). the three study groups regarding endometrial thickness (thickest in G III and thinnest in GI) and endometrial pattern (table 2). group I and the other two groups regarding pregnancy rate (lower in GI) (table 2). the three study groups regarding number of small follicles <14 mm (more in GII and least in GIII). group III and the other two groups regarding number of intermediate follicles (table 2). group I and the other two groups regarding number of dominant follicles (lower in GI) (table 2). There was no statistically significant difference between the three study groups regarding days of stimulation (table 2). group I and the other two groups regarding occurrence of ovulation (lower in GI) (table 2). Discussion Adding phytoestrogens to CC as an alternative to estradiol in women with PCOS have increased number of dominant follicles and improved endometrial thickness and pattern with improvement of both ovulation and pregnancy rates. In our study women received phytoestrogens had more dominant follicles than women received CC only or CC and E2 (2.67± 0.86 vs. 1.42± 0.57 and 2.3±0.84 respectively ) (P value and respectively). In our study women received CC alone had less ovulation rate than women received CC and E2 or CC and phytoestrogens (82% vs. 100% and 100% respectively ) (P value <0.001). We found that women received phytoestrogen had thicker endometrium than those who received CC alone or CC and Page 3 of 5

4 E2 (10.1±1.87 vs. 5.5±1.07 and 9.37±1.75 respectively) while women received E2 with CC had triphasic endometrium more than those who received CC or CC and phytoestrogen (92% vs. 0% and 80% respectively). In our study women received CC alone had lower pregnancy rate than women received CC and E2 or CC and phytoestrogens (18% vs. 34% and 36% respectively ) (P value and respectively ). Shahin and Mohamed studied patients less than 35 years, presenting with infertility and PCOS, were included and randomly allocated to either group I (clomiphene citrate; CC) or group II (CC plus Cimicifugae racemosae; CR. Analysis included 98 patients in group I versus 96 patients in group II. Both groups were matched regarding demographics and basic data. Significant differences were elicited when comparing days until HCG injection (15.0 ± 1.7 versus 12.0 ± 1.9, p = 0.91), endometrial thickness (mm) (8.5 ± 1.9 versus 12.5 ± 1.9, p < 0.001), serum levels of mid-luteal and midcycle estradiol (p < 0.001; Figure 2), LH (IU/ml) (p < 0.001) as well as mid-luteal progesterone (p < 0.001). PE plus CC group had significantly higher clinical pregnancies per cycle (33/192 (17.2%) versus 71/204 (34.8%), p < 0.01), compared to the CC only group. They concluded that adding CR to clomiphene-induction cycles with timed intercourse in polycystic ovarian syndrome improves cycle outcomes and pregnancy rates [10]. Kamel performed a study to evaluate the effects of a phyto-oestrogen, Cimicifuga racimosa extract in induction of ovulation in 100 patients with PCOS. He randomized them into two equal groups the first group received 100 mg of CC per day for 5 days while the second group were subjected to 20 mg of Cimicifuga racimosa extract (Klimadynon) for 10 successive days. The two study groups showed no significant differences regarding demographic data as age or clinically presenting symptoms or hormonal profile measured before the start of the medications. The women in the second group had a significant improvement in the hormonal profile regarding LH level and FSH/LH ratio (p=0.007 and 0.06, respectively) with improvement of progesterone level measured after the first cycle of medication which indicates better ovulation than CC group (p=0.0001). Also a thicker endometrium was found in Cimicifuga racimosa extract group (p=0.0004). A higher but clinically insignificant pregnancy rate was found in Cimicifuga racimosa extract group (p=0.1). He concluded that the use of Phyto-oestrogen is a good alternative to clomiphene citrate for ovulation induction in women with PCOS [11]. Unfer and colleagues in their randomized double blind study evaluated the effect of adding phytoestrogens to CC in induction of ovulation in infertile women subjected to treatment with intrauterine insemination. They selected 134 women complaining of infertility for 2 years or more with their age ranged from 25 to 35 years. All participants had menstrual irregularities in the form of oligomenorrhea or amenorrhea but they all were responsive to progesterone withdrawal test. They randomly classified them into 2 equal groups, group 1 received CC only and group 2 added phytoestrogens to CC. All participants showed increased hormonal levels of FSH, LH and 17-β estradiol in plasma. There was no significant difference between the 2 study groups regarding these hormonal changes. They found a statistically significant difference between the 2 groups regarding endometrial thickness being thicker in group 2. They reached the conclusion that phytoestrogens administered in high doses have the ability to reverse the adverse effects of CC on endometrial thickness with contribution to higher pregnancy rates [12]. Shahin and colleagues randomly classified 134 women with unexplained infertility treated by induction of ovulation using CC into 2 equal groups. Group 1 added phytoestrogen (PE) to CC and group 2 added ethinyl oestradiol (EE) to CC during the proliferative phase Women in PE group needed significantly shorter time to reach adequate maturation of follicles, better endometrial thickness and higher oestradiol concentration at ovulation triggering using human chorionic gonadotrophin injection (all P < 0.001). The serum progesterone level measured during the secretory phase showed a significantly higher level in women who received PE than those received EE. However the clinical pregnancy rate showed no statistically significant difference between the 2 groups (14.0% versus 21.1%, respectively). They concluded that addition of PE during the follicular phase to CC in women with unexplained infertility under treatment of CC ovulation induction and timed natural intercourse markedly improved the cycle characteristics in unexplained infertility women treated with clomiphene citrate induction and timed intercourse when compared with EE supplementation [13]. Page 4 of 5

5 We concluded that adding phytoestrogens to CC as an alternative to estradiol in women with PCOS have increased number of dominant follicles and improved endometrial thickness and pattern with improvement of both ovulation and pregnancy rates Conflict of Interests None. References 1. Hoeger KM. Diagnosis and Management of Polycystic Ovary Syndrome. In Reproductive Endocrinology and Infertility. (Vivian Lewis edi.) LANDES BIOSCIENCE Austin, Texas U.S.A.;2007; Chapter 5 P Moran LJ, Hutchison SK, Norman RJ, Teede HJ: Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2011; 2:CD Homburg R: Management of infertility and prevention of ovarian hyperstimulation in women with polycystic ovary syndrome. Best Prac Res Clin Obstet Gynaecol 2004, 18: Chakraborty P, Goswami SK, Rajani S, Sharma S, Kabir SN, Chakravarty B, et al. Recurrent pregnancy loss in polycystic ovary syndrome: role of hyperhomocysteinemia and insulin resistance. PLoS One 2013; 8:e Havelock JC and Bradshaw KD. Ovulation induction. In Reproductive Endocrinology and Infertility. (Vivian Lewis edi.) LANDES BIOSCIENCE Austin, Texas U.S.A.;2007; Chapter 15 P Homburg R: Clomiphene citrate-end of an era? A mini-review. Hum Reprod 2005; 20: Dehbashi S, Parsanezhad ME, Alborzi S, Zarei A: Effect of clomiphene citrate on endometrium thickness and echogenic patterns. Int J Gynaecol Obstet 2003; 80: Haritha S, Rajagopalan G: Follicular growth, endometrial thickness, and serum estradiol levels in spontaneous and clomiphene citrate-induced cycles. Int J Gynaecol Obstet 2003; 81: The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: Shahin AY, Mohammed SA. Adding the phytoestrogen Cimicifugae Racemosae to clomiphene induction cycles with timed intercourse in polycystic ovary syndrome improves cycle outcomes and pregnancy rates-a randomized trial. Gynecol Endocrinol 2014 Mar Kamel HH. Role of phyto-oestrogens in ovulation induction in women with polycystic ovarian syndrome. Eur J Obstet Gynecol Reprod Biol 2013; 168:1: Unfer V, Casini ML, Costabile L, Mignosa M, Gerli S, Di Renzo GC. High dose of phytoestrogens can reverse the antiestrogenic effects of clomiphene citrate on the endometrium in patients undergoing intrauterine insemination: a randomized trial. J Soc Gynecol Investig 2004; 11:5: Shahin AY, Ismail AM, Shaaban OM. Supplementation of clomiphene citrate cycles with Cimicifuga racemosa or ethinyl oestradiol--a randomized trial. Reprod Biomed Online 2009; 19:4: Page 5 of 5

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