Advertisement
Article| Volume 16, ISSUE 4, P580-588, 2008

Adding phytoestrogens to clomiphene induction in unexplained infertility patients – a randomized trial

      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      This study investigated the role of oral phytoestrogens in improving pregnancy rate and cycle outcomes with clomiphene citrate. Patients with unexplained infertility and recurrent clomiphene citrate induction failure, were randomly divided into two groups: group I (n = 60) and group II (n = 59). Both groups received clomiphene citrate 150 mg per day (days 3 to 7). Group I received additional oral phytoestrogen (Cimicifuga racemosa) 120 mg/day from days 1 to 12. Human chorionic gonadotrophin (HCG) injection (10,000 IU i.m.) was given and timed intercourse was recommended when a leading follicle reached >17 mm and serum oestradiol exceeded 200 (pg/ml). There was a non-significant shortening of induction cycles in group I. Oestradiol and LH concentrations were higher in group I compared with group II. Endometrial thickness, serum progesterone and clinical pregnancy rate were significantly higher in group I (8.9 ± 1.4 mm versus 7.5 ± 1.3 mm, P < 0.001; 13.3 ± 3.1 ng/ml versus 9.3 ± 2.0 ng/ml, P < 0.01; 36.7% versus 13.6%, P < 0.01, respectively). It is concluded that adding C. racemosa rhizome dry extract to clomiphene citrate induction can improve the pregnancy rate and cycle outcomes in these couples.

      Keywords

      References

        • Badawy A
        • Baker El Nashar A
        • El Totongy M
        Clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for augmenting ovulation in the management of unexplained infertility: a randomized double-blind controlled trial.
        Fertility and Sterility. 2006; 86: 647-650
        • Bhattacharya S
        Effective use of assisted reproduction.
        Human Fertility. 2003; 6: 60-62
        • Biteker G
        • Ugur M
        • Deveer R
        The effect of clomiphene citrate on uterine and ovarian blood flow in patients with unexplained infertility. Does estrogen and progesterone treatment reverse these changes?.
        Fertility and Sterility. 2004; 82: S145
        • Bolle P
        • Mastrangelo S
        • Perrone F
        • et al.
        Estrogen-like effect of a Cimicifuga racemosa extract sub-fraction as assessed by in vivo, ex vivo and in vitro assays.
        Journal of Steroid Biochemistry and Molecular Biology. 2007; 107: 262-269
        • Bramlett KS
        • Burris TP
        Target specificity of selective estrogen receptor modulators within human endometrial cancer cells.
        Journal of Steroid Biochemistry and Molecular Biology. 2003; 86: 27-34
        • Brinker F
        Toxicology of Botanical Medicines. Eclectic Medical Publications, Sandy, Oregon2000: 296
        • Casper RF
        Phytoestrogens, clomiphene, and the uterus.
        Journal of the Society for Gynecologic Investigations. 2004; 11: 261-262
        • Chung H
        • Craig AW
        The effect of therapy initiation day on clomiphene citrate therapy.
        Fertility and Sterility. 1989; 52: 564-568
        • Clark JH
        • Markaverich BM
        The agonist-antagonist properties of clomiphene.
        Pharmacology and Therapeutics. 1981; 15: 467-519
        • Collins J
        An international survey of the health economics of IVF and ICSI.
        Human Reproduction Update. 2002; 8: 265-277
        • Cook NC
        • Samman S
        Flavanoids – chemistry, metabolism, cardioprotective effects and dietary sources.
        Journal of Nutritional Biochemistry. 1996; 7: 66-76
        • Diel P
        • Smolnikar K
        • Schulz T
        • et al.
        Phytoestrogens and carcinogenesis – differential effects of genistein in experimental models of normal and malignant rat endometrium.
        Human Reproduction. 2001; 16: 997-1006
        • Diel P
        • Schulz T
        • Smolnikar K
        • et al.
        Ability of xeno- and phytoestrogens to modulate expression of estrogen-sensitive genes in rat uterus: estrogenicity profiles and uterotropic activity.
        Journal of Steroid Biochemistry and Molecular Biology. 2000; 73: 1-10
        • Dorn C
        • Van der Ven H
        Clomiphene citrate versus gonadotrophins for ovulation induction.
        Reproductive Biomedicine Online. 2005; 10: 37-43
        • Dugoua JJ
        • Seely D
        • Perri D
        • et al.
        Safety and efficacy of black cohosh (Cimicifuga racemosa) during pregnancy and lactation.
        Canadian Journal of Clinical Pharmacology. 2006; 13: e257-e261
        • Duker EM
        • Kopanski L
        • Jarry H
        • et al.
        Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats.
        Planta Medica. 1991; 57: 420-424
        • Einer-Jensen N
        • Zhao J
        • Andersen KP
        • et al.
        Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats.
        Maturitas. 1996; 25: 149-153
        • Elnashar A
        • Abdelmageed E
        • Fayed M
        • Sharaf M
        Clomiphene citrate and dexamethazone in treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective placebo-controlled study.
        Human Reproduction. 2006; 21: 1805-1808
        • Farnsworth NR
        • Bingel AS
        • Cordell GA
        • et al.
        Potential value of plants as sources of new antifertility agents I.
        Journal of Pharmaceutical Sciences. 1975; 64: 535-598
        • Fisch P
        • Casper RF
        • Brown SE
        • et al.
        Unexplained infertility: evaluation of treatment with clomiphene citrate and human chorionic gonadotropin.
        Fertility and Sterility. 1989; 51: 828-833
        • Foong SC
        • Fleetham JA
        • O'Keane JA
        • et al.
        A prospective randomized trial of conventional in vitro fertilization versus intracytoplasmic sperm injection in unexplained infertility.
        Journal of Assisted Reproduction and Genetics. 2006; 23: 137-140
        • Foster S
        Black cohosh: Cimicifuga racemosa: a literature review.
        Herbalgram. 1999; 45: 35-50
        • Fujii S
        • Fukui A
        • Fukushi Y
        • et al.
        The effects of clomiphene citrate on normally ovulatory women.
        Fertility and Sterility. 1997; 68: 997-999
        • Gerli S
        • Gholami H
        • Manna C
        • et al.
        Use of ethinyl estradiol to reverse the antiestrogenic effects of clomiphene citrate in patients undergoing intrauterine insemination: a comparative, randomized study.
        Fertility and Sterility. 2000; 73 (Erratum in): 85-89
        • Manna C
        Fertility and Sterility. 2000; 74: 424
        • Glazener CM
        • Coulson C
        • Lambert PA
        • et al.
        Clomiphene treatment for women with unexplained infertility: placebo-controlled study of hormonal responses and conception rates.
        Gynecological Endocrinology. 1990; 4: 75-83
        • Gunn TR
        • Wright IM
        The use of black and blue cohosh in labour.
        New Zealand Medical Journal. 1996; 109: 410-411
        • Guzick DS
        • Grefenstette I
        • Baffone K
        • et al.
        Infertility evaluation in fertile women: a model for assessing the efficacy of infertility testing.
        Human Reproduction. 1994; 9: 2306-2310
        • Han DH
        • Denison MS
        • Tachibana H
        • et al.
        Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids.
        Bioscience, Biotechnology, and Biochemistry. 2002; 66: 1479-1487
        • Harrison EC
        • Taylor JS
        IVF therapy for unexplained infertility.
        American Family Physician. 2006; 73: 63-65
        • Harrison RF
        • O'Moore RR
        The use of clomiphene citrate with and without human chorionic gonadotropin.
        Irish Medical Journal. 1983; 76: 273-274
        • Hernández Muñoz G
        • Pluchino S
        Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer.
        Maturitas. 2003; 14: S59-S65
        • Holzer H
        • Casper R
        • Tulandi T
        A new era in ovulation induction.
        Fertility and Sterility. 2006; 85: 277-284
        • Horstein MD
        • Schust D
        Infertility. Novak's Gynecology. 18th edn. Lippincott Williams and Wilkins Co, Philadelphia1996
        • Hsu CC
        • Kuo HC
        • Wang ST
        • Huang KE
        Interference with uterine blood flow by clomiphene citrate in women with unexplained infertility.
        Obstetrics and Gynecology. 1995; 86: 917-921
        • Jarry H
        • Harnischfeger G
        • Duker E
        The endocrine effects of constituents of Cimicifuga racemosa. 2. In-vitro binding of constituents to estrogen receptors.
        Planta Medica. 1985; 4: 316-319
        • Kelada E
        • Ghani R
        Bilateral ovarian abscesses following transvaginal oocyte retrieval for IVF: a case report and review of literature.
        Journal of Assisted Reproduction and Genetics. 2007; 24: 143-145
        • Kruse SO
        • Lohning A
        • Pauli GF
        • et al.
        Fukiic and piscidic acid esters from the rhizome of Cimicifuga racemosa and the in-vitro estrogenic activity of ukinolic acid.
        Planta Medica. 1999; 65: 763-764
        • Kuiper GG
        • Carlsson B
        • Grandien K
        • et al.
        Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta.
        Endocrinology. 1997; 138: 863-870
        • Liu J
        • Burdette JE
        • Xu H
        • et al.
        Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms.
        Journal of Agricultural and Food Chemistry. 2001; 49: 2472-2479
        • Liu Z
        • Yang Z
        • Zhu M
        • et al.
        Estrogenicity of black cohosh (Cimicifuga racemosa) and its effect on estrogen receptor level in human breast cancer MCF-7 cells.
        Wei sheng yan jiu (Journal of Hygiene Research). 2001; 30: 77-80
        • Mahady GB
        • Fabricant D
        • Chadwick LR
        • Dietz B
        Black cohosh: an alternative therapy for menopause?.
        Nutrition in Clinical Care. 2002; 5: 283-289
        • March CM
        Induction of ovulation.
        in: Lobo RA Mishell DR Paulson RJ Infertility, Contraception, and Reproductive Endocrinology. Blackwell Science, Oxford1992
        • McFarlin BL
        • Gibson MH
        • O'Rear J
        • et al.
        A national survey of herbal preparation use by nurse midwives for labor stimulation. Review of the literature and recommendations for practice.
        Journal of Nurse-Midwifery. 1999; 44: 205-216
        • Nakamura Y
        • Ono M
        • Yoshida Y
        • et al.
        Effects of clomiphene citrate on the endometrial thickness and echogenic pattern of the endometrium.
        Fertility and Sterility. 1997; 67: 256-260
        • Ohno Y
        • Fujimoto Y
        Endometrial oestrogen and progesterone receptors and their relationship to sonographic appearance of the endometrium.
        Human Reproduction Update. 1998; 4: 560-564
        • Salvatori L
        • Pallante P
        • Ravenna L
        • et al.
        Oestrogens and selective oestrogen receptor (ER) modulators regulate EGF receptor gene expression through human ER alpha and beta subtypes via an Sp1 site.
        Oncogene. 2003; 22: 4875-4881
        • Seidlová-Wuttke D
        • Jarry H
        • Viereck V
        • et al.
        Cimicifuga racemosa: a selective estrogen receptor modulator?.
        in: Samsioe G Skouby S Midlife Health: Current Concepts and Challenges for the Future. Elsevier, Amsterdam2001
        • Shahin AY
        The problem of IVF cost in developing countries: has natural cycle IVF a place?.
        Reproductive BioMedicine Online. 2007; 15: 51-56
        • Templeton AA
        • Penney GC
        The incidence, characteristics, and prognosis of patients whose infertility is unexplained.
        Fertility and Sterility. 1982; 37: 175-182
        • The Practice Committee of the American Society for Reproductive Medicine
        Effectiveness and treatment for unexplained infertility.
        Fertility and Sterility. 2006; 86: S111-S114
        • Unfer V
        • Casini ML
        • Costabile L
        • et al.
        High dose of phytoestrogens can reverse the antiestrogenic effects of clomiphene citrate on the endometrium in patients undergoing intrauterine insemination: a randomized trial.
        Journal of the Society of Gynecological Investigations. 2004; 11: 323-328
        • Verhaak CM
        • Smeenk JM
        • Evers AW
        • et al.
        Women's emotional adjustment to IVF: a systematic review of 25 years of research.
        Human Reproduction Update. 2007; 13: 27-36
        • Vlahos NF
        • Coker L
        • Lawler C
        • et al.
        Women with ovulatory dysfunction undergoing ovarian stimulation with clomiphene citrate for intrauterine insemination may benefit from administration of human chorionic gonadotropin.
        Fertility and Sterility. 2005; 83: 1510-1516
        • Winterhoff H
        • Spengler B
        • Christoffel V
        • et al.
        Cimicifuga extract BNO 1055: reduction of hot flushes and hints on antidepressant activity.
        Maturitas. 2003; 14: S51-S58
        • Wuttke W
        • Seidlová-Wuttke D
        • Gorkow C
        The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers.
        Maturitas. 2003; 14: S67-S77
        • Yagel S
        • Ben-Chetrit A
        • Anteby E
        • et al.
        The effect of ethinyl estradiol on endometrial thickness and uterine volume during ovulation induction by clomiphene citrate.
        Fertility and Sterility. 1992; 57: 33-36
        • Zierau O
        • Bodinet C
        • Kolba S
        • et al.
        Antiestrogenic activities of Cimicifuga racemosa extracts.
        Journal of Steroid Biochemistry and Molecular Biology. 2002; 80: 125-130

      Biography

      Dr Ahmed Shahin graduated from Assuit School of Medicine, Egypt in 1995. A scholarship from the German Academic Exchange Organization allowed him to join the endocrinology and infertility management team at Düsseldorf University Medical Centre where he learned clinical and laboratory principles of IVF and completed his MD thesis on laser-assisted hatching of human embryos. He was certified by the German Board OB & Gyn in 2003. Awards include international guest-doctor prize (2002), and international prize for best research design (2006), both from the German Society for Obstetrics and Gynaecology. His specific interests include the improvement of reproductive health, implantation and ovarian tissue cryopreservation.