Objective: Since not all women wish to conceive a child through aggressive treatment, we investigated the usefulness of modified repeated intracyclic clomiphene citrate (CC) therapy (repeated CC therapy) as a newly devised administration method. Methods: We evaluated the effects of CC administration on menstrual cycle length and retrospectively compared ovulation and pregnancy in 220 women who received CC at our hospital. Patients in the conventional method group received 50 mg per day for five days, starting on the fifth day of menstruation (withdrawal bleeding). Groups with and without menstrual cycle shortening after conventional CC administration were compared. The repeated CC therapy group was also compared with the non-shortened group. Repeated CC therapy was administered for the first five days as in the conventional method, and a second five-day repeat treatment was administered after an interval of five to seven days. Pregnancy rates, including indirect pregnancies, were evaluated by three different methods. Results: Ovulation and pregnancy rates were significantly better in the shortened group than in the non-shortened group (P < 0.001 and P = 0.010, respectively). Even in the non-shortened group, ovulation and pregnancy rates including indirect pregnancies were significantly improved when ovulation was observed with repeated CC therapy (P < 0.001 and P = 0.022, respectively). Conclusions: For patients whose menstrual cycle was not improved or shortened, repeated CC therapy as the newly devised CC administration method is useful as the next step after the conventional CC administration method.
References
[1]
The Practice Committee of the American Society for Reproductive Medicine (2013) Use of Clomiphene Citrate in Infertile Women: A Committee Opinion. Fertility and Sterility, 100, 341-348. https://doi.org/10.1016/j.fertnstert.2013.05.033
[2]
Balen, A.H., Morley, L.C., Misso, M., Franks, S., Legro, R.S., Wijeyaratne, C.N., Stener-Victorin, E., Fauser, B.C.J.M., Norman, R.J. and Teede, H. (2016) The Management of Anovulatory Infertility in Women with Polycystic Ovary Syndrome: An Analysis of the Evidence to Support the Development of Global WHO Guidance. Human Reproduction Update, 22, 687-708. https://doi.org/10.1093/humupd/dmw025
[3]
Norman, R.J., Dewailly, D., Legro, R.S. and Hickey, T.E. (2007) Polycystic Ovary Syndrome. TheLancet, 370, 685-697. https://doi.org/10.1016/S0140-6736(07)61345-2
[4]
Ray, A., Shah, A., Gudi, A. and Homburg, R. (2012) Unexplained Infertility: An Update and Review of Practice. Reproductive BioMedicine Online, 24, 591-602. https://doi.org/10.1016/j.rbmo.2012.02.021
[5]
Hughes, E., Brown, J., Collins, J.J. and Vanderkerchove, P. (2010) Clomiphene Citrate for Unexplained Subfertility in Women. Cochrane Database of Systematic Reviews, 2010, CD000057. https://doi.org/10.1002/14651858.CD000057.pub2
[6]
Guzick, D.S., Sulivan, M.W., Adamson, G.D., Cedars, M.I., Falk, R.J., Peterson, E.P. and Steinkampf, M.P. (1998) Efficacy of Treatment for Unexplained Infertility. Fertility and Sterility, 70, 207-213. https://doi.org/10.1016/S0015-0282(98)00177-0
[7]
Weiss, R.V. and Clapauch, R. (2014) Fermale Infertility of Endocrine Origin. Arquivos Brasileiros de Endocrinologia & Metabologia, 58, 144-152. https://doi.org/10.1590/0004-2730000003021
[8]
Carson, S.A. and Kallen, A.N. (2021) Diagnosis and Management of Infertility: A Review. JAMA, 326, 65-76. https://doi.org/10.1001/jama.2021.4788
[9]
Singh, S. and Prakash, U. (2023) Study of Folliculometry after Spontaneous and Clomiphene Citrate-Induced Ovulation in Infertile Women. Cureus, 15, e42234. https://doi.org/10.7759/cureus.42234
[10]
Homburg, R. (2005) Clomiphene Citrate—End of an Era? A Mini-Review. Human Reproduction, 20, 2043-2051. https://doi.org/10.1093/humrep/dei042
[11]
Whitelaw, M.J., Grans, L.R. and Stamm, W.J. (1964) Clomiphene Citrate: It’s Uses and Observations on Its Probable Action. American Journal of Obstetrics & Gynecology, 90, 335-363.
[12]
Markiewicz, L., Laufer, N. and Gurpide, E. (1988) In Vitro Effects of Clomiphene Citrate on Human Endometrium. Fertility and Sterility, 50, 772-776. https://doi.org/10.1016/S0015-0282(16)60314-X
[13]
Weiss, N.S., Nahuis, M., Bayram, N., Mol, B.W., van der Veen, F. and van Wely, M. (2015) Gonadotrophins for Ovulation Induction in Women with Polycystic Ovarian Syndrome. Cochrane Database of Systematic Reviews, 9, CD01029. https://doi.org/10.1002/14651858.CD010290.pub2
[14]
Szilagyi, A., Bartfai, G., Manfai, A., Koloszar, S., Pal, A. and Szabo, I. (2004) Low-Dose Ovulation Induction with Urinary Gonadotropins or Recombinant Follicle Stimulating Hormone in Patients with Polycystic Ovary Syndrome. Gynecological Endocrinology, 18, 17-22. https://doi.org/10.1080/09513590310001651731
[15]
Kelly, A.C. and lewicz, R. (1990) Alternate Regimen for Ovulation Induction Polycystic Ovarian Disease. Fertility and Sterility, 54, 195-202. https://doi.org/10.1016/S0015-0282(16)53688-7
[16]
Moolenaar, L.M., Nahuis, M.J., Hompes, P.G., van der Veen, F. and Mol, B.W.J. (2014) Cost-Effectiveness of Treatment Strategies in Women with PCOS Who do not Conceive after Six Cycles of Clomiphene Citrate. Reproductive BioMedicine Online, 28, 606-613. https://doi.org/10.1016/j.rbmo.2014.01.014
[17]
Tredway, D., Schertz, J.C., Bock, D., Hemsey, G. and Diamond, M. (2011) Anastrozole vs. Clomiphene Citrate in Infertile Women with Ovulatory Dysfunction: A Phase Ⅱ, Randomized Dose-Finding Study. Fertility and Sterility, 95, 1720-1724. https://doi.org/10.1016/j.fertnstert.2010.12.064
[18]
McDwell, S., Kroon, B. and Yazdani, A. (2013) Clomiphene Ovulation Induction and Higher-Order Multiple Pregnancy. Australian and New Zealand Journal of Obstetrics and Gynaecology, 53, 395-398. https://doi.org/10.1111/ajo.12106
[19]
Case, A.M. (2003) Infertility Evaluation and Management. Strategies for Family Physicians. Canadian Family Physician, 49, 1465-1472.
[20]
Kawamura, M., Aoki, Y., Kanda, R., Nakagomi, H., Tsukahara, Y. and Hashimura, N. (2009) Repeated Intracyclic Clomiphene Citrate Therapy Can be More Effective than hMG Therapy in Inducing Ovulation: Case Report. Clinical and Experimental Obstetrics & Gynecology, 36, 82-84.
[21]
Kawamura, M., Satoi, E., Kiyoku, R., Nozaka, N., Matsuda, M., Kanda, R. and Kiseki, H. (2018) Delayed Administration Method of Clomiphene Citrate during the Ovulatory Phase in Patients with a Prolonged Menstrual Cycle. Clinical and Experimental Obstetrics & Gynecology, 45, 299-302. https://doi.org/10.12891/ceog3853.2018
[22]
Lobo, R.A., Gysler, M., March, C.M., Goebelsmann, U. and Mishell Jr., D.R. (1982) Clinical and Laboratory Predictors of Clomiphene Response. Fertility and Sterility, 37, 168-174. https://doi.org/10.1016/S0015-0282(16)46034-6
[23]
Kelekci, S., Saygili-Yilmaz, E., Inan, I. and Eminsoy, G. (2004) A Trial of a New Regimen with Clomiphene Citrate Administration to Reduce the Antiestrogenic Effects on Reproductive End Organs. European Journal of Obstetrics & Gynecology and Reproductive Biology, 116, 54-57. https://doi.org/10.1016/j.ejogrb.2003.12.025
[24]
Bordewijk, E.M., Weiss, N.S., Nahuis, M.J., Bayram, N., van Hooff, M.H.A., Books, D.E.S., (2019) Gonadotropins versus Clomiphene Citrate with or without IUI in Women with Normogonadotropic Anovulation and Clomipnene Failure: A Cost-Effectiveness Analysis. Human Reproduction, 34, 276-284. https://doi.org/10.1093/humrep/dey359
[25]
Kawamura, M., Suzuki, A., Kanda, R., Kiseki, H., Tsukahara, Y. and Hashimura, N. (2012) Modified Repeated Intracyclic Clomiphene Citrate Therapy after Conventional Clomiphene Therapy. Clinical and Experimental Obstetrics & Gynecology, 39, 317-320.
[26]
Vlahos, N.F., Coker, L., Lawler, C., Zhao, Y., Bankowski, B. and Wallach, E. (2005) Women with Ovulatory Dysfunction Undergoing Ovarian Stimulation with Clomiphene Citrate for Intrauterine Insemination May Benefit from Administration of Human Chorionic Gonadotropin. Fertility and Sterility, 83, 1510-1516. https://doi.org/10.1016/j.fertnstert.2004.11.049
[27]
Broughton, D.E. and Moley, K.H. (2017) Obesity and Female Infertility: Potential Mediators of Obesity’s Impact. Fertility and Sterility, 107, 840-847. https://doi.org/10.1016/j.fertnstert.2017.01.017
[28]
Laven, J.S. and Fauser, B.C. (2004) Inhibins and Adult Ovarian Function. Molecular and Cellular Endocrinology, 225, 37-44. https://doi.org/10.1016/j.mce.2004.02.011
[29]
Jose-Miller, A.B., Boyden, J.W. and Frey, K.A. (2007) Infertility. American Family Physician, 75, 849-856.
[30]
Thompson, L.A., Barratt, C.L.R., Thornton, S.J., Bolton, A.E. and Cooke, I.D. (1993) The Effects of Clomiphene Citrate and Cyclofenil on Cervical Mucus Volume and Receptivity over the Periovulatory Period. Fertility and Sterility, 59, 125-129. https://doi.org/10.1016/S0015-0282(16)55627-1
[31]
Wada, M., Kasai, T., Nagai, S., Fujie, M., Miyake, M. and Suzuki, K. (2004) Effect of Repeated Administration of Clomiphene Citrate at Two Different Times on the Endometrium in Patients Undergoing Intrauterine Insemination. Reproductive Medicine and Biology, 3, 153-157. https://doi.org/10.1111/j.1447-0578.2004.00065.x
[32]
Fluker, M.R., Wang, I.Y. and Rowe, T.C. (1996) An Extended 10-Day Course of Clomiphene Citrate (CC) in Women with CC-Resistant Ovulatory Disorders. Fertility and Sterility, 66, 761-764. https://doi.org/10.1016/S0015-0282(16)58632-4
[33]
Fisch, P., Casper, R.F., Brown, S.E., Wrixon, W., Collins, J.A., Reid, R.L. and Slimpson, C. (1989) Unexplained Infertility: Evalution of Treatment with Clomiphene Citrate and Human Chorionic Gonadotropin. Fertility and Sterility, 51, 828-833. https://doi.org/10.1016/S0015-0282(16)60674-X
[34]
Budinetz, T.H., Benadiva, C.A., Griffin, D.W., Engmann, L.L., Nulsen, J.C. and DiLuigi, A.J. (2015) Ovulation Rate and Cycle Characteristics in a Subsequent Clomiphene Citrate Cycle after Stair-Step Protocol. Fertility and Sterility, 103, 675-679. https://doi.org/10.1016/j.fertnstert.2014.12.088
[35]
Hurst, B.S., Hickman, J.M., Matthews, M.L., Usadi, R.S. and Marshburn, P.B. (2009) Novel Clomiphene “Stair-Step” Protocol Reduces Time to Ovulation in Women with Polycystic Ovarian Syndrome. American Journal of Obstetrics & Gynecology, 200, 510.E1-E4. https://doi.org/10.1016/j.ajog.2008.10.031
