- Mark D Hornstein, MD
Mark D Hornstein, MD
- Professor of Obstetrics, Gynecology & Reproductive Biology
- Harvard Medical School
- William E Gibbons, MD
William E Gibbons, MD
- Division of Reproductive Endocrinology
- Department of Obstetrics and Gynecology
- Baylor College of Medicine
- Chief of Reproductive Medicine for the Pavilion for Women
- Texas Children's Hospital
It is relatively simple to identify the cause of infertility in women with ovulatory disorders or tubal disease, and in men with semen abnormalities. These categories account for the source of infertility in approximately 75 percent of couples. Infertility in the remaining 25 percent of couples is due to endometriosis (8 percent) or miscellaneous factors (eg, cervical factor, immunological factor, uterine synechiae) (2 percent) or is unexplained (15 percent) [1-3].
Management of couples with unexplained infertility will be reviewed here. Diagnosis and treatment of known causes of infertility are discussed separately. (See "Overview of infertility" and "Pathogenesis and treatment of infertility in women with endometriosis" and "Evaluation of male infertility" and "Treatment of male infertility".)
DEFINITION AND DIAGNOSIS
Unexplained infertility refers to the absence of a definable cause for a couple's failure to achieve pregnancy after 12 months of attempting conception despite a thorough evaluation, or after six months in women 35 and older [4,5]. Authorities vary in their concept of what constitutes a thorough evaluation, and these opinions have evolved over time. Currently, a thorough evaluation typically includes documentation of:
- Collins JA, Crosignani PG. Unexplained infertility: a review of diagnosis, prognosis, treatment efficacy and management. Int J Gynaecol Obstet 1992; 39:267.
- Templeton AA, Penney GC. The incidence, characteristics, and prognosis of patients whose infertility is unexplained. Fertil Steril 1982; 37:175.
- Guzick DS, Grefenstette I, Baffone K, et al. Infertility evaluation in fertile women: a model for assessing the efficacy of infertility testing. Hum Reprod 1994; 9:2306.
- Moghissi KS, Wallach EE. Unexplained infertility. Fertil Steril 1983; 39:5.
- Practice Committee of tAmerican Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 90:S60.
- Blacker CM, Ginsburg KA, Leach RE, et al. Unexplained infertility: evaluation of the luteal phase; results of the National Center for Infertility Research at Michigan. Fertil Steril 1997; 67:437.
- Leach RE, Moghissi KS, Randolph JF, et al. Intensive hormone monitoring in women with unexplained infertility: evidence for subtle abnormalities suggestive of diminished ovarian reserve. Fertil Steril 1997; 68:413.
- Guzick DS, Carson SA, Coutifaris C, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. N Engl J Med 1999; 340:177.
- Pandian Z, Bhattacharya S, Vale L, Templeton A. In vitro fertilisation for unexplained subfertility. Cochrane Database Syst Rev 2005; :CD003357.
- Hull MG. Effectiveness of infertility treatments: choice and comparative analysis. Int J Gynaecol Obstet 1994; 47:99.
- Lessey BA. Assessment of endometrial receptivity. Fertil Steril 2011; 96:522.
- Smith JF, Eisenberg ML, Millstein SG, et al. Fertility treatments and outcomes among couples seeking fertility care: data from a prospective fertility cohort in the United States. Fertil Steril 2011; 95:79.
- SART clinic summary report 2013 https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0.
- Marcoux S, Maheux R, Bérubé S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997; 337:217.
- Diamond MP, Legro RS, Coutifaris C, et al. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. N Engl J Med 2015; 373:1230.
- Sunderam S, Kissin DM, Crawford SB, et al. Assisted Reproductive Technology Surveillance — United States, 2012. MMWR Surveill Summ 2015; 64:1.
- Letrozole prescribing information https://www.nlm.nih.gov/medlineplus/druginfo/meds/a698004.html (Accessed on December 17, 2015).
- Miravet-Valenciano JA, Rincon-Bertolin A, Vilella F, Simon C. Understanding and improving endometrial receptivity. Curr Opin Obstet Gynecol 2015; 27:187.
- Chang J, Boulet SL, Jeng G, et al. Outcomes of in vitro fertilization with preimplantation genetic diagnosis: an analysis of the United States Assisted Reproductive Technology Surveillance Data, 2011-2012. Fertil Steril 2016; 105:394.
- Evers JL. Female subfertility. Lancet 2002; 360:151.
- Hull MG, Glazener CM, Kelly NJ, et al. Population study of causes, treatment, and outcome of infertility. Br Med J (Clin Res Ed) 1985; 291:1693.
- Steures P, van der Steeg JW, Hompes PG, et al. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial. Lancet 2006; 368:216.
- Custers IM, van Rumste MM, van der Steeg JW, et al. Long-term outcome in couples with unexplained subfertility and an intermediate prognosis initially randomized between expectant management and immediate treatment. Hum Reprod 2012; 27:444.
- Barbieri RL. The initial fertility consultation: recommendations concerning cigarette smoking, body mass index, and alcohol and caffeine consumption. Am J Obstet Gynecol 2001; 185:1168.
- Wittemer C, Ohl J, Bailly M, et al. Does body mass index of infertile women have an impact on IVF procedure and outcome? J Assist Reprod Genet 2000; 17:547.
- Fedorcsák P, Dale PO, Storeng R, et al. Impact of overweight and underweight on assisted reproduction treatment. Hum Reprod 2004; 19:2523.
- Hughes E, Brown J, Collins JJ, Vanderkerchove P. Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev 2010; :CD000057.
- Fisch P, Casper RF, Brown SE, et al. Unexplained infertility: evaluation of treatment with clomiphene citrate and human chorionic gonadotropin. Fertil Steril 1989; 51:828.
- Guzick DS, Sullivan MW, Adamson GD, et al. Efficacy of treatment for unexplained infertility. Fertil Steril 1998; 70:207.
- Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: a committee opinion. Fertil Steril 2013; 100:341.
- Bhattacharya S, Harrild K, Mollison J, et al. Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomised controlled trial. BMJ 2008; 337:a716.
- Merrill Dow Pharmaceuticals. Product information bulletin. Cincinnati Ohio 1972.
- Collins J. Global epidemiology of multiple birth. Reprod Biomed Online 2007; 15 Suppl 3:45.
- Cantineau AE, Cohlen BJ, Heineman MJ. Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility. Cochrane Database Syst Rev 2007; :CD005356.
- Kosmas IP, Tatsioni A, Fatemi HM, et al. Human chorionic gonadotropin administration vs. luteinizing monitoring for intrauterine insemination timing, after administration of clomiphene citrate: a meta-analysis. Fertil Steril 2007; 87:607.
- Cantineau AE, Heineman MJ, Cohlen BJ. Single versus double intrauterine insemination (IUI) in stimulated cycles for subfertile couples. Cochrane Database Syst Rev 2003; :CD003854.
- Osuna C, Matorras R, Pijoan JI, Rodríguez-Escudero FJ. One versus two inseminations per cycle in intrauterine insemination with sperm from patients' husbands: a systematic review of the literature. Fertil Steril 2004; 82:17.
- Polyzos NP, Tzioras S, Mauri D, Tatsioni A. Double versus single intrauterine insemination for unexplained infertility: a meta-analysis of randomized trials. Fertil Steril 2010; 94:1261.
- Ragni G, Maggioni P, Guermandi E, et al. Efficacy of double intrauterine insemination in controlled ovarian hyperstimulation cycles. Fertil Steril 1999; 72:619.
- Randall GW, Gantt PA. Double vs. single intrauterine insemination per cycle: use in gonadotropin cycles and in diagnostic categories of ovulatory dysfunction and male factor infertility. J Reprod Med 2008; 53:196.
- Custers IM, Steures P, Hompes P, et al. Intrauterine insemination: how many cycles should we perform? Hum Reprod 2008; 23:885.
- Dovey S, Sneeringer RM, Penzias AS. Clomiphene citrate and intrauterine insemination: analysis of more than 4100 cycles. Fertil Steril 2008; 90:2281.
- Liu A, Zheng C, Lang J, Chen W. Letrozole versus clomiphene citrate for unexplained infertility: a systematic review and meta-analysis. J Obstet Gynaecol Res 2014; 40:1205.
- Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014; 371:119.
- Tulandi T, Martin J, Al-Fadhli R, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006; 85:1761.
- Practice Committee of American Society for Reproductive Medicine. Multiple gestation associated with infertility therapy: an American Society for Reproductive Medicine Practice Committee opinion. Fertil Steril 2012; 97:825.
- Reindollar RH, Regan MM, Neumann PJ, et al. A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertil Steril 2010; 94:888.
- Kansal-Kalra S, Milad MP, Grobman WA. In vitro fertilization (IVF) versus gonadotropins followed by IVF as treatment for primary infertility: a cost-based decision analysis. Fertil Steril 2005; 84:600.
- Pandian Z, Gibreel A, Bhattacharya S. In vitro fertilisation for unexplained subfertility. Cochrane Database Syst Rev 2012; :CD003357.
- Goldman MB, Thornton KL, Ryley D, et al. A randomized clinical trial to determine optimal infertility treatment in older couples: the Forty and Over Treatment Trial (FORT-T). Fertil Steril 2014; 101:1574.
- Aboulghar MA, Mansour RT, Serour GI, et al. Management of long-standing unexplained infertility: A prospective study. Am J Obstet Gynecol 1999; 181:371.
- Hughes E, Collins J, Vandekerckhove P. Bromocriptine for unexplained subfertility in women. Cochrane Database Syst Rev 2000; :CD000044.
- Hughes E, Tiffin G, Vandekerckhove P. Danazol for unexplained infertilty. Cochrane Database Syst Rev 2000; :CD000069.
- DEFINITION AND DIAGNOSIS
- POSSIBLE ETIOLOGIES
- OUR APPROACH
- EXPECTANT MANAGEMENT
- PATIENT-CONTROLLED APPROACHES
- Lifestyle changes
- LOW-RESOURCE INTERVENTIONS
- Intrauterine insemination
- Clomiphene citrate
- Clomiphene plus IUI
- Aromatase inhibitors plus IUI
- HIGH-RESOURCE INTERVENTIONS
- Gonadotropin injections with or without IUI
- In vitro fertilization
- ALTERNATIVE TO IN VITRO FERTILIZATION
- INEFFECTIVE TREATMENTS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS