European Journal of Obstetrics & Gynecology and Reproductive Biology 168 (2013) 60–63 Contents lists available at SciVerse ScienceDirect European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb Role of phyto-oestrogens in ovulation induction in women with polycystic ovarian syndrome Hany H. Kamel * Department of Obstetrics and Gynaecology, Faculty of Medicine, Minia University, Minia, Egypt A B S T R A C T Article history: Received 13 March 2012 Received in revised form 30 September 2012 Accepted 28 December 2012 Objective: To study the role of a phyto-oestrogen, Cimicifuga racimosa extract (Klimadynon1, Bionorica, Neumarkt i.d.OBf., Germany), in ovulation induction in women with polycystic ovarian syndrome (PCOS). Study design: Prospective randomized controlled trial in Minia University Hospital, Minia, Egypt. One hundred women with PCOS were allocated into one of two groups: one group (n = 50) received clomiphene citrate 100 mg daily for 5 days, and the other group (n = 50) received C. racimosa 20 mg daily for 10 days. Both groups received medication starting from the second day of the cycle for three consecutive cycles, during which changes in follicle-stimulating hormone (FSH), luteinizing hormone (LH), FSH/LH ratio, progesterone, endometrial thickness and pregnancy rate were measured. Results: The groups were similar in terms of age, clinical presentation and hormonal levels before treatment. Following treatment, signiﬁcant favourable changes in LH level and FSH/LH ratio (p = 0.007 and 0.06, respectively) were seen in the Klimadynon group. In this group the progesterone level was higher from the ﬁrst treatment cycle, indicating better ovulation (p = 0.0001), and endometrial thickness was greater (p = 0.0004). The pregnancy rate was higher in the Klimadynon group but the difference between the groups was not signiﬁcant (p = 0.1). Conclusion: Phyto-oestrogen can be used as an alternative to clomiphene citrate for ovulation induction in women with polycystic ovarian syndrome. ß 2013 Elsevier Ireland Ltd. All rights reserved. rC DR A R T I C L E I N F O Co pi 1. Introduction aa ut or iza da po Keywords: Clomiphene citrate Phyto-oestrogen PCOS Ovulation induction Polycystic ovarian syndrome (PCOS), ﬁrst described in 1935 by Stein and Leventhal, is the most common endocrinopathy in women of reproductive age, with a prevalence of approximately 6.5%. Its cardinal features are hyperandrogenism and polycystic ovaries [1]. Clinically, PCOS is characterized by menstrual irregularities, hyperandrogenism, hyperinsulinaemia and longterm metabolic disturbances (e.g. diabetes mellitus, cardiovascular disease, and dyslipidaemia) [2]. Risk factors include history of premature adrenarche, family history of PCOS and history of perimenarchal weight gain [3]. In 2006, the Androgen Excess Society proposed a new set of diagnostic criteria for PCOS, as follows: (1) clinical and/or biochemical signs of hyperandrogenism and exclusion of other aetiologies and (2) ovulatory dysfunction as demonstrated by oligo-ovulation/anovulation or polycysticappearing ovaries [4]. * Tel.: +20 101204427; fax: +20 86342503. E-mail address: [email protected]. For many years, the ﬁrst line of pharmacological ovulation induction has involved the use of selective oestrogen receptor modulators [5]. Clomiphene citrate (CC) has been studied most extensively: the ﬁrst trial of CC resulted in successful ovulation induction in approximately 80% of women, and half were ultimately able to achieve pregnancy [6]. CC has many sideeffects, however, including increased risk of multiple pregnancy (to 8%), undesirable anti-oestrogenic effects in the endocervix, endometrium and ovary which help explain the discrepancy between ovulation and conception rates, vasomotor ﬂushes (in up to 10% of cycles), mood swings, visual disturbances, breast tenderness, pelvic discomfort and nausea [7]. There is therefore a need for other inducing agents with good ovulatory rates and fewer side-effects. One agent that needs to be studied is Cimicifuga racimosa (black cohosh) extract. C. racimosa is popular as an alternative to hormonal therapy for the treatment of menopausal (climacteric) symptoms such as hot ﬂushes, mood disturbances, diaphoresis, palpitations and vaginal dryness. Several studies have used C. racimosa to improve menopausal symptoms for up to six months, although the evidence is mixed [8]. The oestrogenic effect of C. racemosa is evident, but its mechanism of action and its receptor selectivity have not been well 0301-2115/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejogrb.2012.12.025 14/07/2014 H.H. Kamel / European Journal of Obstetrics & Gynecology and Reproductive Biology 168 (2013) 60–63 3. Results DR Fig. 1 shows a ﬂowchart of the study including enrolment, allocation, follow-up and analysis. Demographic characteristics were comparable between the Klimadynon group and the CC group in terms of age (years) (23 2.3 vs. 24 2.66; p = 0.4) and body mass index (in kg/m2) (26 1.7 vs. 25 2.33; p = 0.2) (Table 1). Before treatment, no statistical differences were found between the two groups in terms of FSH, LH or FSH/LH ratio. Following treatment, however, remarkable hormonal changes were seen in the Klimadynon group, particularly in LH level and FSH/LH ratio, with a marked reduction in LH level (ﬁrst cycle 8.5 0.28 vs. 8.9 0.55; p = 0.0001), and this signiﬁcant difference was present in all three treatment cycles (Table 2). The progesterone level was higher in the Klimadynon group than the CC group, especially in the ﬁrst cycle (10.12 0.14 vs. 9.54 0.15 ng/ml; p = 0.0001). Endometrial thickness was greater in iza da This prospective randomized controlled study was conducted in the Department of Obstetrics and Gynaecology, Faculty of Medicine, Minia University, Minia, Egypt from August 2009 to April 2010 following approval by the Department’s Ethical Committee. One hundred women with PCOS were recruited from the attendees of the Gynaecology Clinic at Minia University Hospital. Written informed consent was obtained from each woman prior to participation in the study. The women were divided at random into two groups: one group (n = 50) received Klimadynon, 20 mg twice daily orally for 10 days, starting from the second day of the cycle, repeated for three successive cycles; and one group (control, n = 50) received CC 50 mg twice daily for 5 days, starting from the second day of the cycle, repeated for three successive cycles. All women were subjected to history taking, general examination, local pelvic examination, transvaginal ultrasound examination to document ultrasound criteria of PCOS, and blood sampling to measure FSH, LH and mid-luteal progesterone levels on basal day 3. Following each course of Klimadynon or CC, blood samples were obtained from all patients to re-assess the levels of FSH, LH and progesterone. Transvaginal ultrasound evaluation was rC 2. Materials and methods performed on day 14 to document the number and size of the growing follicles, and endometrial thickness. Human chorionic gonadotrophin was given when the leading follicle reached 18 mm or more, when timed intercourse was advised. The two groups were compared in terms of clinical characteristics and hormonal levels before and after treatment. Correlation between serum FSH, LH and FSH/LH ratio was performed. In addition, the incidence and degree of ovarian hyper-stimulation were assessed, and the pregnancy rate was also compared and statistically analyzed. Data were collected and tabulated using Excel Version 7 (Microsoft Corporation, New York, NY, USA), and analyzed using Statistical Package for the Social Sciences Version 11 (SPSS Inc., Chicago, IL, USA). po studied. Accordingly, it may have an oestrogen-like effect at a central level, and may therefore antagonize the natural endogenous oestrogen as a competitor. As such, it could be used for ovulation induction in women with PCOS. This study aimed to study the role of C. racemosa (Klimadynon1, Bionorica, Neumarkt i.d.OBf., Germany) in women with PCOS in terms of ovulation induction, hormonal proﬁle correction and pregnancy rate. 61 Co pi aa ut or Assessed for eligibility (n=100) Enrolment 100 patients with PCOS (age 21–27 years) with either primary or secondary infertility were divided at random into two groups using computer-generated random numbers and sealed envelopes Klimadynon group (n=50) 20 mg Klimadynon for 10 days from second day of the cycle Analysed (n=50) Seven cases excluded from analysis at the end of the third cycle CC group (n=50) Allocation Analysis Received CC 50 mg daily for 5 days from second day of the cycle Analysed (n=50) Four cases excluded from analysis at the end of the third cycle Fig. 1. Flowchart of study procedure including patients’ enrolment, allocation, follow-up and analysis. CC, clomiphene citrate; PCOS, polycystic ovarian syndrome. 14/07/2014 H.H. Kamel / European Journal of Obstetrics & Gynecology and Reproductive Biology 168 (2013) 60–63 62 Table 1 Sociodemographic criteria of patients. Parameters Klimadynon group (n = 50) Clomiphene citrate group (n = 50) p-Value Age (years) Primary infertility Secondary infertility Body mass index 23 2.3 36 (48%) 14 (56%) 26 1.7 24 2.66 39 (52%) 11 (44%) 25 2.33 0.4 0.3 0.2 0.2 Table 2 Responses to treatment for both groups. Before treatment After treatment p-Value First cycle Third cycle Klimadynon group (n = 50) CC group (n = 50) Klimadynon group (n = 48) CC group (n = 49) Klimadynon group (n = 45) CC group (n = 47) Klimadynon group (n = 43) CC group (n = 46) 5.3 0.22 9.5 0.62 1.7 0.45 6.63 0.589 4.9 0.85 9.6 0.65 1.95 0.33 6.58 0.233 5.6 0.56 8.5 0.28 1.03 0.98 10.12 0.14 5.3 0.36 8.9 0.55 1.7 0.73 9.54 0.15 5.2 0.44 5.5 0.28 1.05 0.34 11.16 0.857 5.3 0.36 6.9 0.55 1.3 0.55 11.2 0.352 5.92 0.63 3.45 0.14 0.582 0.21 11.98 0.416 5.65 0.28 4.55 0.16 0.805 0.82 11.96 0.251l 3.1 3.2 8.34 6.89 9.67 6.34 0 0 0 0 2 1 1 0 3 0 2 1 CC, clomiphene citrate; FSH, follicle-stimulating hormone; LH, luteinizing hormone. 2 0 0.0001 0.007 0.06 0.0001 7.32 0.0004 1 1 0.1 0.22 da po effect of Klimadynon on the endometrium, which improves the implantation rate and pregnancy outcome. This ﬁnding was in agreement with Casper [9] and Unfer et al. [10], who reported a signiﬁcant increase in endometrial thickness among women receiving phyto-oestrogens. Treatment of women with PCOS with C. racimosa extract led to an earlier and higher pregnancy rate compared with CC treatment, but this difference was not signiﬁcant. This difference may be attributed to the sample size, and it is possible that a signiﬁcant difference could be obtained in a larger study. A higher pregnancy rate was also evident in a study that used C. racimosa extract as adjuvant therapy with CC in patients with unexplained infertility [11]. Further studies are needed in the near future to document the agonistic/antagonistic effects of C. racimosa extract on different oestrogenic receptors in different body systems, and to conﬁrm the direct and indirect effects of C. racimosa extract on these receptors. Also, there is a need to study the effect of C. racimosa extract on cervical mucus when used alone or as adjuvant therapy with CC. Finally, there is a need to study the optimum duration of use of C. racimosa extract, especially in older patients and pre- and postmenopausal women, due to its prominent uterotrophic effect and the possibility of inducing endometrial hyperplasia or even endometrial carcinoma. In conclusion, although Klimadynon induced ovulation in women with PCOS with fewer side-effects compared with CC, more studies are needed to conﬁrm these data, and to determine the optimum dose and duration of this novel protocol. 4. Comments aa ut or iza the Klimadynon group than the CC group (ﬁrst cycle: 8.34 vs. 6.89 mm; second cycle: 9.67 vs. 6.34 mm; third cycle: 9.11 vs. 7.32 mm; p = 0.0004). The pregnancy rate was higher in the Klimadynon group than the CC group, but this difference was not signiﬁcant (7 vs. 4 pregnancies; p = 0.1). There were two twin pregnancies in the Klimadynon group and one twin pregnancy in the CC group (p = 0.2), and one case of abortion in the Klimadynon group. Overall, there were three cases of hyperstimulation: one mild case in the Klimadynon group, one mild case in the CC group and one moderate case in the CC group. This difference was not signiﬁcant. 9.11 DR FSH (IU/ml) LH (IU/ml) FSH/LH Progesterone (ng/ml) Endometrial thickness (mm) Pregnancy rate Hyperstimulation Second cycle rC Parameters Co pi This randomized controlled trial compared two treatment modalities, Klimadynon and CC, for ovulation induction in women with PCOS. Klimadynon treatment resulted in a signiﬁcant reduction in LH level and LH/FSH ratio. This was evident in the ﬁrst treatment cycle and continued throughout all treatment cycles. This is in accordance with Wuttke et al., who reported that C. racimosa extract acted directly on the hypothalamus to reduce the release of gonadotrophin-releasing hormone, and therefore reduce the level of LH in the circulation. Wuttke et al. ruled out a direct effect of C. racimosa extract on the pituitary, as C. racimosa extract had no direct effect on LH release in pituitary tissue of ovariectomized rats in vitro [8]. Acute treatment with C. racimosa extract 62.5 mg resulted in a reduction in serum LH level, compared with control and oestrogen-treated ovariectomized rats. This indicates that compounds in C. racimosa extract affect the hypothalamo-pituitary axis, which results in less pituitary LH secretion [8]. A reduction in LH has a remarkable effect on the symptoms of excessive androgens experienced by women with PCOS, allowing better ovulation and implantation rates. In addition, reduction of the LH level increases the sensitivity of ovarian tissue to circulating FSH, improving follicular growth, ovulation and implantation. This study found good ovulation rates from the ﬁrst treatment cycle with Klimadynon. Endometrial thickness increased in response to either endogenous induced oestrogen or the direct Acknowledgements The authors wish to thank all staff members at the Department of Obstetrics and Gynaecology and the laboratory team at the Faculty of Medicine, Minia University, Egypt. The authors also wish to thank Mr. Mohammed Hamdy for editing the manuscript, and Mrs. Sherin Hassan for helping with statistics. References [1] Laven JS, Imani B, Eijkemans MJ, Fauser BC. New approach to polycystic ovary syndrome and other forms of anovulatory infertility. Obstetrical and Gynecological Survey 2002;57:755–67. 14/07/2014 H.H. Kamel / European Journal of Obstetrics & Gynecology and Reproductive Biology 168 (2013) 60–63 [7] Shams T, Setia MS, Hemmings R, McCusker J, Sewitch M, Ciampi A. Efﬁcacy of black cohosh-containing preparations on menopausal symptoms: a metaanalysis. Alternative Therapies in Health and Medicine 2010;16:36–44. [8] Wuttke W, Jarry H, Seidlova´-Wuttke D. Cimicifuga racemosa extract for the treatment of climacteric complaints. Journal of Endocrinology and Reproduction 2006;10:106–10. [9] Casper RF. Phytoestrogen, clomiphene and the uterus. Journal of the Society for Gynecologic Investigation 2004;11:261–2. [10] Unfer V, Casini ML, Costabile L, et al. High dose of phytoestrogens can reverse the antiestrogenic effect of clomiphene citrate on the endometrium in patients undergoing intrauterine insemination: a randomized trial. Journal of the Society for Gynecologic Investigation 2004;11:323–8. [11] Shaheen AY, Ismail AM, Zahran KM, Makhlouf A. Adding phytoestrogens to clomiphene induction in unexplained infertility patients – a randomized trial. Reproductive Biomedicine 2008;16:580–8. Co pi aa ut or iza da po rC DR [2] Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. American Journal of Medicine 1995;98:33S–9S. [3] Guzick DS, Hoeger K. Polycystic ovary syndrome Clinical updates in women’s health care, vol. 8(1). Washington, DC: American College of Obstetricians and Gynecologists; 2009. [4] Azziz R, Carmina E, Dewailly D, et al. Criteria for deﬁning polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society Guideline. Journal of Clinical Endocrinology and Metabolism 2006;91:4237–45. [5] Greenblatt RB. Chemical induction of ovulation. Fertility and Sterility 1961;12: 402–4. [6] Correy JF, Marsden DE, Schokman FCM. The outcome of pregnancy resulting from clomiphene-induced ovulation therapy. Australian and New Zealand Journal of Obstetrics and Gynaecology 1982;22:1–64. 63 14/07/2014