Oral Agents for Ovulation Induction

Year 2022, Volume: 24 Issue: Special Issue, 90 - 96, 30.10.2022

Raziye Narin

https://doi.org/10.18678/dtfd.1185208

Abstract

Infertility due to ovulation disorders is 25% of all infertility causes. The most common cause of ovulation disorders is patients with normogonadatropic normogonadism, which is group II according to the World Health Organization anovulation classification and mostly consists of patients with polycystic ovary syndrome which affects 6-20% of women of reproductive age. Oral ovulation induction agents are a suitable option only for patients in this group. The purpose of the ovulation induction is to stimulate the ovaries for monofollicular development. Oral agents used in ovulation induction can be divided into two groups, selective estrogen receptor modulators and aromatase inhibitors as first-line agents, and metformin and inositols as second-line agents. The aim of this review is to compare the use and efficacy of the primary oral ovulation induction agents, clomiphene citrate and letrozole, and also to reveal the contributions of the adjuvant drugs metformin and inositol. It is seen that letrozole is superior to clomiphene citrate in polycystic ovary syndrome and is currently preferred as the first-choice drug worldwide. Metformin alone increases the ovulation rate compared to placebo in women with polycystic ovary syndrome, but should not be used as first-line therapy for anovulation. Similarly, when inositol is used alone, it does not increase the pregnancy rate.

Keywords

Anovulation, polycystic ovary syndrome, clomiphene citrate, letrozole, metformin, inositol

Ovulasyon İndüksiyonunda Oral Ajanlar

Abstract

Ovulasyon bozukluklarına bağlı infertilite, tüm infertilite nedenlerinin %25'ini oluşturmaktadır. Ovulasyon bozukluklarının en sık nedeni, Dünya Sağlık Örgütü anovulasyon sınıflamasına göre grup II olan ve çoğunlukla üreme çağındaki kadınların %6-20'sini etkileyen polikistik over sendromlu hastalardan oluşan normogonadatropik normogonadizmli hastalardır. Oral ovulasyon indüksiyon ajanları sadece bu gruptaki hastalar için uygun bir seçenektir. Ovulasyon indüksiyonunun amacı, yumurtalıkları monofoliküler gelişim için uyarmaktır. Ovulasyon indüksiyonunda kullanılan oral ajanlar, birinci basamak ajanlar olarak selektif östrojen reseptör modülatörleri ve aromataz inhibitörleri ve ikinci basamak ajanlar olarak metformin ve inositoller olmak üzere iki gruba ayrılabilir. Bu derlemenin amacı, birincil oral ovulasyon indüksiyon ajanları olan klomifen sitrat ve letrozolün kullanım ve etkinliklerini karşılaştırmak ve ayrıca adjuvan ilaçlar olan metformin ve inositolün katkılarını ortaya koymaktır. Polikistik over sendromunda letrozolün klomifen sitrata göre daha üstün olduğu ve günümüzde dünya çapında ilk seçenek ilaç olarak tercih edildiği görülmektedir. Polikistik over sendromlu kadınlarda, tek başına metformin plaseboya kıyasla ovulasyon oranını arttırır, ancak anovulasyon için birinci basamak tedavi olarak kullanılmamalıdır. Benzer şekilde, inositol tek başına kullanıldığında gebelik oranını artırmamaktadır.

Keywords

Anovulasyon, polikistik over sendromu, klomifen sitrat, letrozol, metformin, inositol

References

• National Institute for Health and Care Excellence. Fertility: assessment and treatment for people with fertility problems. NICE clinical guideline 156; 2013.
• Crosignani PG, Bianchedi D, Riccaboni A, Vegetti W. Management of anovulatory infertility. Hum Reprod 1999;14(Suppl 1):108-19.
• Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14(5):270-84.
• Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016;2:16057.
• Ding DC, Chen W, Wang JH, Lin SZ. Association between polycystic ovarian syndrome and endometrial, ovarian, and breast cancer: A population-based cohort study in Taiwan. Medicine (Baltimore). 2018;97(39):e12608.
• Zhang C, Ma J, Wang W, Sun Y, Sun K. Lysyl oxidase blockade ameliorates anovulation in polycystic ovary syndrome. Hum Reprod. 2018;33(11):2096-106.
• Norman RJ, Teede HJ. A new evidence-based guideline for assessment and management of polycystic ovary syndrome. Med J Aust. 2018;209(7):299-300.
• Ells LJ, Rees K, Brown T, Mead E, Al-Khudairy L, Azevedo L, et al. Interventions for treating children and adolescents with overweight and obesity: an overview of Cochrane reviews. Int J Obes (Lond). 2018;42(11):1823-33.
• Vegetti W, Guermandi E, Baroni E, Alagna F, Riccaboni A, Nicolosi AE, et al. [Induction of monofollicular cycles]. Minerva Ginecol. 2001;53(1):41-8. Italian.
• van Rumste MM, Custers IM, van der Veen F, van Wely M, Evers JL, Mol BW. The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: a meta-analysis. Hum Reprod Update. 2008;14(6):563-70.
• Nozaki M. [SERM]. Nihon Rinsho. 2006;64(9):1645-50. Japanese.
• Jie L, Li D, Yang C, Haiying Z. Tamoxifen versus clomiphene citrate for ovulation induction in infertile women. Eur J Obstet Gynecol Reprod Biol. 2018;228:57-64.
• de Paula Guedes Neto E, Savaris RF, von Eye Corleta H, de Moraes GS, do Amaral Cristovam R, Lessey BA. Prospective, randomized comparison between raloxifene and clomiphene citrate for ovulation induction in polycystic ovary syndrome. Fertil Steril. 2011;96(3):769-73.
• Glasier AF, Irvine DS, Wickings EJ, Hillier SG, Baird DT. A comparison of the effects on follicular development between clomiphene citrate, its two separate isomers and spontaneous cycles. Hum Reprod. 1989;4(3):252-6.
• Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update. 1996;2(6):483-506.
• Scaparrotta A, Chiarelli F, Verrotti A. Potential teratogenic effects of clomiphene citrate. Drug Saf. 2017;40(9):761-9.
• Kettner LO, Matthiesen NB, Ramlau-Hansen CH, Kesmodel US, Henriksen TB. Fertility treatment with clomiphene citrate and childhood epilepsy: a nationwide cohort study. Hum Reprod. 2021;36(9):2567-75.
• Yu Q, Lv X, Liu K, Ma D, Wu Y, Dai W, et al. Fertility drugs associated with thyroid cancer risk: a systematic review and meta-analysis. Biomed Res Int. 2018;2018:7191704.
• Adashi EY. Clomiphene citrate: mechanism(s) and site(s) of action--a hypothesis revisited. Fertil Steril. 1984;42(3):331-44.
• Eden JA, Place J, Carter GD, Jones J, Alaghband-Zadeh J, Pawson ME. The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume. Obstet Gynecol. 1989;73(2):187-90.
• Dehbashi S, Parsanezhad ME, Alborzi S, Zarei A. Effect of clomiphene citrate on endometrium thickness and echogenic patterns. Int J Gynaecol Obstet. 2003;80(1):49-53.
• Montenegro IS, Kuhl CP, Schneider RA, Zachia SA, Durli ICLO, Terraciano PB, et al. Use of clomiphene citrate protocol for controlled ovarian stimulation impairs endometrial maturity. JBRA Assist Reprod. 2021;25(1):90-6.
• Roumen FJ. [Decreased quality of cervix mucus under the influence of clomiphene: a meta-analysis]. Ned Tijdschr Geneeskd. 1997;141(49):2401-5. Dutch.
• Quaas AM, Gavrizi SZ, Peck JD, Diamond MP, Legro RS, Robinson RD, et al. Endometrial thickness after ovarian stimulation with gonadotropin, clomiphene, or letrozole for unexplained infertility, and association with treatment outcomes. Fertil Steril. 2021;115(1):213-20.
• Dodge ST, Strickler RC, Keller DW. Ovulation induction with low doses of clomiphene citrate. Obstet Gynecol. 1986;67(3 Suppl):63S-5S.
• Palatnik A, Strawn E, Szabo A, Robb P. What is the optimal follicular size before triggering ovulation in intrauterine insemination cycles with clomiphene citrate or letrozole? An analysis of 988 cycles. Fertil Steril. 2012;97(5):1089-94.e1-3.
• Lobo RA, Granger LR, Davajan V, Mishell DR Jr. An extended regimen of clomiphene citrate in women unresponsive to standard therapy. Fertil Steril. 1982;37(6):762-6.
• Hurst BS, Hickman JM, Matthews ML, Usadi RS, Marshburn PB. Novel clomiphene "stair-step" protocol reduces time to ovulation in women with polycystic ovarian syndrome. Am J Obstet Gynecol. 2009;200(5):510.e1-4.
• Horowitz E, Weissman A. The stair-step approach in treatment of anovulatory PCOS patients. Ther Adv Reprod Health. 2020;14:2633494120908818.
• Diamond MP, Kruger M, Santoro N, Zhang H, Casson P, Schlaff W, et al. Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome. Obstet Gynecol. 2012;119(5):902-8.
• Dickey RP, Taylor SN, Curole DN, Rye PH, Pyrzak R. Incidence of spontaneous abortion in clomiphene pregnancies. Hum Reprod. 1996;11(12):2623-8.
• Blakemore J, Naftolin F. Aromatase: contributions to physiology and disease in women and men. Physiology (Bethesda). 2016;31(4):258-69.
• Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003;348(24):2431-42.
• Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349(19):1793-802.
• Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM. An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane. Cancer. 2002;95(9):2006-16.
• Holzer H, Casper R, Tulandi T. A new era in ovulation induction. Fertil Steril. 2006;85(2):277-84.
• Weil S, Vendola K, Zhou J, Bondy CA. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab. 1999;84(8):2951-6.
• Kranc W, Budna J, Kahan R, Chachuła A, Bryja A, Ciesiółka S, et al. Molecular basis of growth, proliferation, and differentiation of mammalian follicular granulosa cells. J Biol Regul Homeost Agents. 2017;31(1):1-8.
• Franks S, Adams J, Mason H, Polson D. Ovulatory disorders in women with polycystic ovary syndrome. Clin Obstet Gynaecol. 1985;12(3):605-32.
• Al-Fadhli R, Sylvestre C, Buckett W, Tan SL, Tulandi T. A randomized trial of superovulation with two different doses of letrozole. Fertil Steril. 2006;85(1):161-4.
• Bansal S, Goyal M, Sharma C, Shekhar S. Letrozole versus clomiphene citrate for ovulation induction in anovulatory women with polycystic ovarian syndrome: A randomized controlled trial. Int J Gynaecol Obstet. 2021;152(3):345-50.
• Tsiami AP, Goulis DG, Sotiriadis AI, Kolibianakis EM. Higher ovulation rate with letrozole as compared with clomiphene citrate in infertile women with polycystic ovary syndrome: a systematic review and meta-analysis. Hormones (Athens). 2021;20(3):449-61.
• Akbari Sene A, Ghorbani S, Ashrafi M. Comparison of the pregnancy outcomes and the incidence of fetal congenital abnormalities in infertile women treated with letrozole and clomiphene citrate. J Obstet Gynaecol Res. 2018;44(6):1036-41.
• Diamond MP, Mitwally M, Casper R, Ager J, Legro RS, Brzyski R, et al. Estimating rates of multiple gestation pregnancies: sample size calculation from the assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial. Contemp Clin Trials. 2011;32(6):902-8.
• Mejia RB, Summers KM, Kresowik JD, Van Voorhis BJ. A randomized controlled trial of combination letrozole and clomiphene citrate or letrozole alone for ovulation induction in women with polycystic ovary syndrome. Fertil Steril. 2019;111(3):571-8.e1.
• Nardo LG, Rai R. Metformin therapy in the management of polycystic ovary syndrome: endocrine, metabolic and reproductive effects. Gynecol Endocrinol. 2001;15(5):373-80.
• Practice Committee of the American Society for Reproductive Medicine. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertil Steril. 2017;108(3):426-41.
• Vucenik I. Bioactivity of inositol phosphates. Molecules. 2021;26(16):5042.
• Gerli S, Mignosa M, Di Renzo GC. Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial. Eur Rev Med Pharmacol Sci. 2003;7(6):151-9.
• Kamenov Z, Gateva A. Inositols in PCOS. Molecules. 2020;25(23):5566.
• Showell MG, Mackenzie-Proctor R, Jordan V, Hodgson R, Farquhar C. Inositol for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2018;12(12):CD012378.
• Franik S, Eltrop SM, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2018;5(5):CD010287.
• Check JH, Liss JR, Vaniver J. The effect of clomiphene citrate vs. letrozole on post-coital tests. Clin Exp Obstet Gynecol. 2016;43(2):184-5.
• Sakar MN, Oğlak SC. Comparison of the efficacy of letrozole stair-step protocol with clomiphene citrate stair-step protocol in the management of clomiphene citrate-resistant polycystic ovary syndrome patients. J Obstet Gynaecol Res. 2021;47(11):3875-82.
• Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551-66.