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Ovulation induction with letrozole

Ovulation induction with letrozole
Literature review current through: Jan 2024.
This topic last updated: Aug 11, 2022.

INTRODUCTION — Women with polycystic ovary syndrome (PCOS) often have anovulatory infertility. Clomiphene citrate is the most commonly used pharmacologic agent to induce ovulation in these women, but some women fail to conceive with this therapy. During the past decade, aromatase inhibitors have been explored as an option for ovulation induction in women who fail to conceive with clomiphene citrate. Aromatase inhibitors are a class of drugs that block estrogen biosynthesis, thereby reducing negative estrogenic feedback at the pituitary.

This topic reviews the use of letrozole, the most effective aromatase inhibitor, for ovulation induction in women with PCOS and as an adjunct to gonadotropin therapy for controlled ovarian hyperstimulation (COH) in women with ovulatory infertility. The use of clomiphene and gonadotropins is reviewed separately. (See "Ovulation induction with clomiphene citrate" and "Overview of ovulation induction".)

PHARMACOLOGY AND PHYSIOLOGY — Aromatase is a microsomal cytochrome P450 hemoprotein-containing enzyme (P450arom, the product of the CYP19 gene) that catalyzes the rate-limiting step in the production of estrogens: the conversion of androstenedione and testosterone via three hydroxylation steps to estrone and estradiol, respectively [1]. It is a good target for selective inhibition because estrogen production is a terminal step in the biosynthetic sequence. Aromatase activity is present in many tissues, including the ovaries, brain, adipose tissue, muscle, liver, and breast.

Aromatase inhibitors are widely used as adjuvant endocrine therapy for postmenopausal women with breast cancer. They have been used off-label in the treatment of patients with anovulatory infertility [2], such as polycystic ovary syndrome (PCOS), and for increasing the number of ovarian follicles recruited in ovulatory women undergoing controlled ovarian hyperstimulation (COH) [3,4]. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and 'Ovulation induction in PCOS' below and 'Controlled ovarian hyperstimulation' below.)

Letrozole and anastrozole are triazole (antifungal) derivatives that are potent, reversible, competitive, nonsteroidal aromatase inhibitors [5,6]. In postmenopausal women, at doses of 1 to 5 mg/day, these drugs inhibit estrogen biosynthesis by 97 to >99 percent, resulting in estrogen concentrations below the levels detected by most sensitive immunoassays. They are completely absorbed after oral administration and have a mean terminal half-life of approximately 45 hours (range 30 to 60 hours); clearance is mainly hepatic. By comparison, exemestane, a steroidal aromatase inhibitor, has a circulating half-life of approximately nine hours, but the inhibitory effect is potentially much longer because its effect on aromatase is irreversible [7].

Administration of an aromatase inhibitor to premenopausal women on days 3 to 7 of the menstrual cycle results in suppression of ovarian estradiol secretion, a rise in follicle-stimulating hormone (FSH) (due to release from the negative feedback effect of estradiol), follicular development, and estradiol production (as the effect of the aromatase inhibitor diminishes). As the dominant follicle grows and estrogen levels rise, normal negative feedback occurs centrally because aromatase inhibitors do not deplete estrogen receptors in the brain [8,9]. FSH is then suppressed, and the smaller-growing follicles become atretic, resulting in monofollicular ovulation in most cases (figure 1). The potential for mono-ovulation represents a theoretical advantage over clomiphene citrate, which is associated with an increased risk of multiple gestation. (See "Ovulation induction with clomiphene citrate", section on 'Outcomes'.)

The addition of FSH to an aromatase inhibitor is necessary to achieve multiple ovulation, the desired goal in the setting of COH or in vitro fertilization (IVF). (See 'Controlled ovarian hyperstimulation' below.)

CLINICAL USES OF LETROZOLE — As noted, aromatase inhibitors (most commonly, letrozole) have been used off-label in the treatment of patients with anovulatory infertility, such as polycystic ovary syndrome (PCOS) [10-14], and for increasing the number of ovarian follicles in ovulatory women undergoing controlled ovarian hyperstimulation (COH).

Letrozole is unlikely to be successful in women with hypothalamic amenorrhea or ovarian failure as they are already hypoestrogenemic at baseline. Alternative treatments should be considered for these patients, such as exogenous gonadotropin therapy for women with hypogonadotropic hypogonadism and oocyte donation for women with ovarian failure (primary ovarian insufficiency). (See "Overview of ovulation induction", section on 'Gonadotropin therapy' and "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?'.)

There have been concerns about the use of aromatase inhibitors for ovulation induction because they could disrupt the normal aromatase activity during early fetal development and therefore be potentially teratogenic if administered inadvertently during early pregnancy. This issue is discussed below. (See 'Fetal safety' below.)

Ovulation induction in PCOS — Letrozole is now considered to be the drug of choice for ovulation induction in women with PCOS. Clomiphene citrate has been the first-line drug for this population for many years, with metformin used as an alternative. However, both clomiphene and metformin appear to be less effective for live birth rates than letrozole [15]. (See 'Comparison with clomiphene' below and "Metformin for treatment of the polycystic ovary syndrome", section on 'Anovulatory infertility'.)

Ovulatory disorders are identified in up to 25 percent of couples presenting with infertility. Most of these women have oligomenorrhea, defined as menstruation that occurs at intervals of ≥35 days, and the most common diagnosis among women with oligomenorrhea is polycystic ovary syndrome (PCOS) (see "Diagnosis of polycystic ovary syndrome in adults"). While ovulation may occasionally occur, spontaneous conception is unlikely. Induction of ovulation in these women is aimed at inducing monofollicular development, subsequent ovulation, and, ultimately, pregnancy and birth of a healthy newborn. (See "Overview of ovulation induction".)

Letrozole regimen — If an aromatase inhibitor is prescribed for ovulation induction in a patient with PCOS, we suggest letrozole over anastrozole as letrozole has been more extensively studied and appears to be more effective over a wide range of doses [4,5,16-18]. Anastrazole is now rarely, if ever, used for ovulation induction.

When prescribing letrozole, the starting dose is 2.5 mg/day, cycle days 3 to 7, following a spontaneous menses or progestin-induced bleed. If the cycle is ovulatory, but pregnancy has not occurred, the same dose should be used in the next cycle. If ovulation does not occur, the dose should be increased to 5 mg/day, cycle days 3 to 7, with a maximal dose of 7.5 mg/day. Sequential dose escalation of 2.5, 5, and 7.5 mg if ovulation does not occur on lower doses is widely used by reproductive endocrinologists [19,20].

Higher doses (7.5 mg) appear to be associated with a thinning of the endometrium similar to that seen with clomiphene citrate [12]. Two proof-of-concept studies have reported that a single-dose regimen (20 mg) may also be effective [21,22], but we do not suggest this approach at this time, as data are limited and further studies are underway.

Comparison with clomiphene — Clomiphene citrate, a selective estrogen receptor modulator, has been used for ovulation induction since the 1960s. It has been considered to be first-line therapy for women with PCOS. However, some women do not ovulate with clomiphene citrate, some experience adverse antiestrogenic endometrial effects, and there is an increased risk of multiple gestation (twins 6 to 9 percent, triplet pregnancies are rare). (See "Ovulation induction with clomiphene citrate", section on 'Polycystic ovary syndrome'.)

Potential advantages of letrozole over clomiphene citrate include [18]:

A high rate of monofollicular development, which should theoretically reduce the risk of multiple pregnancies.

A shorter half-life (48 hours versus two weeks for clomiphene citrate), which would predict a lower risk of teratogenicity.

No direct antiestrogenic adverse effects on the endometrium, due to an absence of peripheral estrogen receptor blockade and the shorter half-life.

Lower serum estradiol levels – This is a particular advantage for women with breast cancer undergoing ovarian stimulation prior to gonadotoxic therapy and possibly for women with endometriosis undergoing in vitro fertilization (IVF), but this is speculative. (See 'Women with breast cancer' below and "Fertility preservation: Cryopreservation options", section on 'Patients with estrogen-sensitive cancer'.)

Outcomes — Available data suggest that letrozole is superior to clomiphene citrate for the outcome of live birth rates in oligo-ovulatory women with PCOS [20,23,24]. Early data suggested that clomiphene and letrozole resulted in similar ovulatory and pregnancy rates [25,26]. However, a randomized trial [20] and a meta-analysis of 14 trials in nearly 3000 anovulatory women with PCOS [23] suggest that letrozole therapy results in higher live birth rates compared with clomiphene therapy.

The trial was a multicenter study in 750 women with PCOS (diagnosed using modified Rotterdam criteria), who were randomly assigned to receive five days of letrozole (2.5 mg) or clomiphene citrate (50 mg) beginning on cycle day 3 for up to five cycles [20]. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Rotterdam criteria (preferred)'.)

If ovulation did not occur, the dose could be increased in the subsequent cycle. Results included the following:

The cumulative live birth rate was higher in the letrozole group (103 of 374 [27.5 percent]) compared with the clomiphene group (72 of 376 [19.1 percent]) (relative risk [RR] 1.44, 95% CI 1.10-1.87). The live birth rate of 19.1 percent with clomiphene citrate (mean body mass index [BMI] of subjects was 35 kg/m2) was considerably lower than previously reported rates in women with PCOS using clomiphene citrate (38 percent in a prospective cohort study of 240 women with a mean BMI of 26 kg/m2) [27].

The cumulative ovulation rate was also higher with letrozole (834 of 1354 treatment cycles [62 percent] versus 688 of 1425 treatment cycles [48 percent]; RR 1.28, 95% CI 1.19-1.37).

BMI had a significant impact on live birth rates:

For women with a BMI ≤30.3 kg/m2, the cumulative live birth rate (approximately 30 percent) was similar in the clomiphene and letrozole groups.

For women with a BMI ≥30.3 kg/m2, the cumulative live birth rate was significantly higher with letrozole when compared with clomiphene (20 versus 10 percent). The women with obesity in both treatment groups had lower live birth rates than women without obesity, consistent with previous ovulation induction trials demonstrating a negative impact of obesity on fecundity [27]. (See "Ovulation induction with clomiphene citrate", section on 'Patient selection'.)

Miscarriage rates were similar with the two therapies (49 of 154 pregnancies in the letrozole group [31.8 percent] versus 30 of 103 pregnancies in the clomiphene citrate group [29.1 percent]). There were no differences in birth weights or rates of neonatal complications (including anomalies). (See 'Fetal safety' below.)

The twin pregnancy rate was lower with letrozole (4 of 117 [3.4 percent]) than with clomiphene (6 of 81 [7.4 percent]), but the study was underpowered to detect a significant difference between the two groups.

In a 2018 meta-analysis of 14 trials comparing letrozole and clomiphene citrate monotherapy [23] (including the multicenter trial [20]), letrozole was more effective than clomiphene for live birth rates (n = 2954 patients; odds ratio [OR] 1.68, 95% CI 1.42-1.99; number needed to treat [NNT] for an additional live birth was 10). There were no differences in rates of miscarriage or multiple pregnancies between the two therapies.

Unlike the multicenter trial that reported a higher live birth rate with letrozole only in women with obesity and BMI greater than 30 kg/m2 [20], a subgroup analysis of the pooled trials in the meta-analysis observed no significant impact of a mean BMI above or below 25 kg/m2 on the primary outcome (live birth rate) [23].

The American College of Obstetrics and Gynecology (ACOG) has published revised recommendations for the choice of ovulation induction agents in women with PCOS [24]. While they previously suggested letrozole as first-line therapy (over clomiphene citrate) only for women with a BMI >30 kg/m2 [20], they now recommend it for all women with PCOS, regardless of BMI. In addition, they recommend lifestyle changes and weight loss for all women with PCOS and obesity to try to restore ovulatory cycles without the use of ovulation induction agents.

Although high-order multiple births would not be anticipated with letrozole, the first case of sextuplets with letrozole ovulation induction has been reported [28]. A 32-year-old woman with PCOS, anovulatory infertility, and an antral follicle count >50 underwent clomiphene citrate (50 mg) therapy without success (no ovulation and poorly tolerated side effects). She was switched to letrozole and had no response to 2.5 or 5 mg, but developed five follicles on 7.5 mg. Although the patient was advised to abstain from intercourse, she did not; at seven weeks, she was noted to have a sextuplet pregnancy. The pregnancy was reduced to twins, but she experienced pregnancy loss at 19 weeks. This case highlights the importance of ultrasound monitoring with ovulation induction to assess follicular number and cancel cycles when necessary.

Side effects — In the trial noted above [20], common side effects included hot flashes in 33 percent of women receiving clomiphene and fatigue and dizziness in 22 and 12 percent, respectively, of women taking letrozole.

In contrast to the relatively mild side effects with short-term use of letrozole for ovulation induction, the use of aromatase inhibitors as adjuvant endocrine therapy for postmenopausal women with breast cancer has been associated with musculoskeletal symptoms in at least one-third of patients. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Side effects'.)

Fetal safety — There have been concerns about the use of aromatase inhibitors for ovulation induction because they could disrupt the normal aromatase activity during early fetal development and therefore be potentially teratogenic if administered inadvertently during early pregnancy. Although animal data suggest that aromatase inhibitors could be associated with teratogenicity [29], human studies have not observed teratogenic risks that are greater than those for clomiphene use [20,30-34]. A theoretical advantage of letrozole is its short half-life when compared with clomiphene citrate. Letrozole is cleared before ovulation occurs, while clomiphene may still be present during fertilization and early embryo development. However, most studies have reported similar rates of congenital malformations with the two therapies.

Data on fetal safety with aromatase inhibitors in over 1800 pregnancies include the following:

A study comparing the incidence of congenital malformations in 911 newborns of women who conceived following treatment with letrozole or clomiphene citrate did not find a statistically significant difference [30]. Congenital malformations were diagnosed in 14 of 514 (2.4 percent) newborns in the letrozole group versus 19 of 397 (4.8 percent) newborns in the clomiphene group; the rates of major malformations were similar (1.2 and 3 percent, respectively). The rate of all congenital cardiac anomalies was higher in the clomiphene group (7 of 397 [1.8 percent]) compared with the letrozole group (1 of 514 [0.2 percent]), but numbers were small.

A follow-up study by the Motherisk Program at the Hospital for Sick Children in Toronto found no increase in congenital anomalies with either letrozole (0 of 94 infants [0 percent]) or clomiphene (7 of 271 infants [2.6 percent]) compared with a control group of spontaneous conceptions (3 of 112 infants [3.2 percent]), but it did observe a significant increase in low birth weight infants with use of clomiphene [31]. Infants born after use of letrozole were similar in birth weight to infants conceived spontaneously.

In one of the trials described above [20], the rate of overall congenital anomalies was not significantly different between the letrozole and clomiphene groups (5 of 102 infants [4.9 percent] and 1 of 66 infants [1.5 percent], respectively). However, there were four major congenital anomalies in the letrozole group compared with only one in the clomiphene group.

In two other studies, the rates of congenital malformations in infants born to mothers who had received letrozole versus clomiphene for ovulation induction were similar:

5 of 104 (4.8 percent) and 3 of 142 (2.1 percent) [32]

5 of 201 (2.5 percent) and 10 of 251 (3.9 percent) [34]

Other data on congenital anomalies with clomiphene use are reviewed separately. The majority of studies suggest that the rate of congenital anomalies with clomiphene is similar to that for spontaneous pregnancies. (See "Ovulation induction with clomiphene citrate", section on 'Perinatal outcome'.)

Suggested approach — For anovulatory women with PCOS who are overweight or obese, we suggest weight loss, prior to initiating ovulation induction therapy. The approach to obesity management is the same as that for patients without PCOS, starting with lifestyle interventions (diet and exercise), followed by pharmacotherapy (if not pursuing pregnancy), and, when necessary, bariatric surgery. (See "Treatment of polycystic ovary syndrome in adults", section on 'Weight reduction' and "Obesity in adults: Overview of management" and "Outcomes of bariatric surgery", section on 'Polycystic ovary syndrome'.)

For women who are unable to lose weight, our approach to ovulation induction for anovulatory women with PCOS is consistent with clinical practice guidelines on aromatase inhibitors for ovulation induction in PCOS [24,35], and it includes the following:

We suggest letrozole as first-line therapy over clomiphene citrate. The starting dose is 2.5 mg administered days 3 to 7; this can be titrated up to a maximum dose of 7.5 mg/day if ovulation has not occurred. However, before starting letrozole, the clinician must discuss with the patient that this is use of the drug is not FDA approved and that there is an alternative (clomiphene citrate) that is FDA approved.

This is the approach used by both authors of this topic. One of the topic editors has a slightly different approach: While letrozole is first-line therapy for women with PCOS and obesity, they allow patients without obesity choose between letrozole or clomiphene citrate after explaining that letrozole is not FDA approved for this use.

Although evidence thus far suggests that letrozole is not associated with an increased risk of congenital malformations, safety data are based upon approximately 1800 pregnancies, a relatively small number. In contrast, clomiphene citrate is approved for ovulation induction and has been widely used for over 40 years. The majority of clinical trial and epidemiologic studies suggest that the rate of congenital anomalies is similar to that for spontaneous pregnancies, and longitudinal follow-up of children born to mothers who took clomiphene citrate have no evidence of developmental delays or learning disabilities. (See "Ovulation induction with clomiphene citrate", section on 'Perinatal outcome'.)

Based on the half-life of letrozole, administration in the early follicular phase should result in clearance of letrozole before implantation takes place. Nevertheless, as with any ovulation induction agent, one must confirm that the patient is not pregnant before starting therapy. We suggest a blood pregnancy test before administering letrozole.

Controlled ovarian hyperstimulation

Unexplained infertility — Letrozole plus intrauterine insemination (IUI) has been used for women with unexplained (ovulatory) infertility who do not respond to clomiphene citrate plus IUI and who cannot or choose not to use IVF or gonadotropin therapy. (See "Unexplained infertility", section on 'Aromatase inhibitors plus IUI'.)

Letrozole has also been used alone or as an adjunct to gonadotropin therapy in women with unexplained infertility. The addition of letrozole to gonadotropin therapy appears to reduce the dose of follicle-stimulating hormone (FSH) required to achieve optimal COH, without adverse antiestrogenic effects [10,36-39]. In one report, the addition of letrozole (or clomiphene citrate) was associated with a decrease in the mean number of oocytes and an increase in cycle cancellations [40]. However, in a second report, the addition of letrozole to gonadotropins (compared with gonadotropins alone) during IVF resulted in a greater number of oocytes and blastocysts, similar pregnancy rates, and no increased risk of ovarian hyperstimulation syndrome [41,42]. (See "Unexplained infertility", section on 'Aromatase inhibitors plus IUI' and "In vitro fertilization: Overview of clinical issues and questions".)

Women with breast cancer — It is desirable to avoid high serum estrogen concentrations in women with breast cancer undergoing ovarian stimulation for cryopreservation of embryos or oocytes prior to gonadotoxic therapy. Letrozole plus FSH therapy is associated with significantly lower serum estrogen levels at midcycle than clomiphene citrate plus FSH and with a reduction of exogenous FSH requirements [37,43]. Therefore, we suggest the addition of letrozole to FSH in women with breast cancer undergoing ovarian stimulation. (See 'Controlled ovarian hyperstimulation' above and "Fertility preservation: Cryopreservation options", section on 'Patients with estrogen-sensitive cancer'.)

Women with endometrial cancer — The strategy of combining letrozole and FSH therapy to avoid high serum estradiol concentrations described for women with breast cancer undergoing ovarian stimulation for cryopreservation of embryos or oocytes prior to gonadotoxic therapy or definitive surgery has also been used for women with endometrial carcinoma. (See 'Women with breast cancer' above and "Fertility preservation: Cryopreservation options", section on 'Patients with estrogen-sensitive cancer'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Polycystic ovary syndrome" and "Society guideline links: Female infertility".)

SUMMARY AND RECOMMENDATIONS

Use in women with PCOS For oligo-ovulatory women with polycystic ovary syndrome (PCOS) undergoing ovulation induction, we suggest letrozole as first-line therapy over clomiphene citrate (Grade 2C), because it is associated with higher live birth rates. (See 'Ovulation induction in PCOS' above and 'Comparison with clomiphene' above.)

Impact of BMI – The greatest advantage in live birth rates with letrozole appears to be in women with a body mass index (BMI) ≥30 kg/m2. Before starting letrozole, the clinician must discuss that this use of the drug is not US Food and Drug Administration (FDA) approved and that there is an available alternative. (See 'Suggested approach' above.)

Safety Most studies have reported similar rates of congenital malformations with letrozole and clomiphene citrate. However, we perform a blood pregnancy test prior to administering letrozole in premenopausal women. (See 'Fetal safety' above and 'Suggested approach' above.)

Other indications In women with breast cancer undergoing follicle-stimulating hormone (FSH) therapy for ovarian stimulation for cryopreservation of embryos or oocytes prior to undergoing gonadotoxic therapy, we suggest the addition of letrozole (Grade 2C). (See 'Women with breast cancer' above.)

  1. Cole PA, Robinson CH. Mechanism and inhibition of cytochrome P-450 aromatase. J Med Chem 1990; 33:2933.
  2. Malloch L, Rhoton-Vlasak A. An assessment of current clinical attitudes toward letrozole use in reproductive endocrinology practices. Fertil Steril 2013; 100:1740.
  3. Casper RF, Mitwally MF. A historical perspective of aromatase inhibitors for ovulation induction. Fertil Steril 2012; 98:1352.
  4. Bedaiwy MA, Mousa NA, Esfandiari N, et al. Follicular phase dynamics with combined aromatase inhibitor and follicle stimulating hormone treatment. J Clin Endocrinol Metab 2007; 92:825.
  5. Buzdar A, Howell A. Advances in aromatase inhibition: clinical efficacy and tolerability in the treatment of breast cancer. Clin Cancer Res 2001; 7:2620.
  6. Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol 2002; 20:3317.
  7. Mauras N, Lima J, Patel D, et al. Pharmacokinetics and dose finding of a potent aromatase inhibitor, aromasin (exemestane), in young males. J Clin Endocrinol Metab 2003; 88:5951.
  8. Kamat A, Hinshelwood MM, Murry BA, Mendelson CR. Mechanisms in tissue-specific regulation of estrogen biosynthesis in humans. Trends Endocrinol Metab 2002; 13:122.
  9. Naftolin F. Brain aromatization of androgens. J Reprod Med 1994; 39:257.
  10. Sammour A, Biljan MM, Tan SL, Tulandi T. Prospective randomized trial comparing the effects of letrazole (LE) and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation prior to intrauterine insemination (IUI). Fertil Steril 2001; 76:S110.
  11. Cortínez A, De Carvalho I, Vantman D, et al. Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients. Fertil Steril 2005; 83:110.
  12. Al-Fozan H, Al-Khadouri M, Tan SL, Tulandi T. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril 2004; 82:1561.
  13. Fatemi HM, Kolibianakis E, Tournaye H, et al. Clomiphene citrate versus letrozole for ovarian stimulation: a pilot study. Reprod Biomed Online 2003; 7:543.
  14. Al-Omari WR, Sulaiman WR, Al-Hadithi N. Comparison of two aromatase inhibitors in women with clomiphene-resistant polycystic ovary syndrome. Int J Gynaecol Obstet 2004; 85:289.
  15. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356:551.
  16. Tredway D, Schertz JC, Bock D, et al. Anastrozole single-dose protocol in women with oligo- or anovulatory infertility: results of a randomized phase II dose-response study. Fertil Steril 2011; 95:1725.
  17. Tredway D, Schertz JC, Bock D, et al. Anastrozole vs. clomiphene citrate in infertile women with ovulatory dysfunction: a phase II, randomized, dose-finding study. Fertil Steril 2011; 95:1720.
  18. Casper RF, Mitwally MF. Review: aromatase inhibitors for ovulation induction. J Clin Endocrinol Metab 2006; 91:760.
  19. Al-Fadhli R, Sylvestre C, Buckett W, et al. A randomized trial of superovulation with two different doses of letrozole. Fertil Steril 2006; 85:161.
  20. 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.
  21. Mitwally MF, Casper RF. Single-dose administration of an aromatase inhibitor for ovarian stimulation. Fertil Steril 2005; 83:229.
  22. Biljan MM, Tkalec DD, Lachgar H. A study comparing a single dose of 25mg of letrazole given on day 3 of menstrual cycle with a daily dose of 5mg of letrazole given between day 3 and day 7 of menstrual cycle in patients with unexplained infertility: Prospective randomized double blind trial. Fertil Steril 2004; 82:S81.
  23. Franik S, Eltrop SM, Kremer JA, et al. Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev 2018; 5:CD010287.
  24. ACOG Committee Opinion No. 738: Aromatase Inhibitors in Gynecologic Practice. Obstet Gynecol 2018; 131:1.
  25. Badawy A, Abdel Aal I, Abulatta M. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial. Fertil Steril 2009; 92:849.
  26. He D, Jiang F. Meta-analysis of letrozole versus clomiphene citrate in polycystic ovary syndrome. Reprod Biomed Online 2011; 23:91.
  27. Imani B, Eijkemans MJ, te Velde ER, et al. A nomogram to predict the probability of live birth after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. Fertil Steril 2002; 77:91.
  28. Warraich G, Vause TD. First reported case of sextuplets conceived via letrozole for ovulation induction. Fertil Steril 2015; 103:535.
  29. Tiboni GM. Aromatase inhibitors and teratogenesis. Fertil Steril 2004; 81:1158.
  30. 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.
  31. Forman R, Gill S, Moretti M, et al. Fetal safety of letrozole and clomiphene citrate for ovulation induction. J Obstet Gynaecol Can 2007; 29:668.
  32. 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; 44:1036.
  33. Tatsumi T, Jwa SC, Kuwahara A, et al. No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole use in assisted reproductive technology. Hum Reprod 2017; 32:125.
  34. Sharma S, Ghosh S, Singh S, et al. Congenital malformations among babies born following letrozole or clomiphene for infertility treatment. PLoS One 2014; 9:e108219.
  35. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018; 110:364.
  36. Mitwally MF, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril 2002; 77:776.
  37. Mitwally MF, Casper RF. Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in women with unexplained infertility. Hum Reprod 2003; 18:1588.
  38. Mitwally MF, Casper RF. Aromatase inhibition reduces the dose of gonadotropin required for controlled ovarian hyperstimulation. J Soc Gynecol Investig 2004; 11:406.
  39. Healey S, Tan SL, Tulandi T, Biljan MM. Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination. Fertil Steril 2003; 80:1325.
  40. Kamath MS, Maheshwari A, Bhattacharya S, et al. Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation. Cochrane Database Syst Rev 2017; 11:CD008528.
  41. Haas J, Casper RF. In vitro fertilization treatments with the use of clomiphene citrate or letrozole. Fertil Steril 2017; 108:568.
  42. Haas J, Bassil R, Meriano J, et al. Does daily co-administration of letrozole and gonadotropins during ovarian stimulation improve IVF outcome? Reprod Biol Endocrinol 2017; 15:70.
  43. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001; 75:305.
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