The use of aromatase inhibitors in infertility and gynecology

Abstract

Aromatase inhibitors act by blocking the aromatization of androgen to estrogen. Although the concentration of estrogen is decreased, they do not have the antiestrogen effect of clomiphene. This makes them ideal for ovulation induction and controlled ovarian hyperstimulation. Owing to their ability to decrease estrogen concentration, aromatase inhibitors could also be used for estrogen-dependent conditions including endometriosis, myoma and adenomyosis. In addition, they could be useful for stimulation of follicle development in women with estrogen-dependent neoplasia who wish to preserve their fertility.

Keywords::

• aromatase inhibitor
• endometriosis
• fertility preservation
• letrozole
• myoma
• ovulation induction

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Release date: July 27, 2011; Expiration date: July 27, 2012

Learning objectives

• • Evaluate the use of aromatase inhibitors in the management of infertility.

• • Describe the current role of aromatase inhibitors among women receiving assisted reproductive technology.

• • Analyze the safety of aromatase inhibitors in the management of infertility.

• • Distinguish the efficacy of aromatase inhibitors in the treatment of endometriosis and uterine myomas.

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHOR AND CREDENTIALS

Jana Al-Shalati

Department of Obstetrics and Gynecology, McGill University, 687 Pine Avenue West, Montreal, QC, H3A 1A1, Canada.

Disclosure: Jana Al-Shalati has disclosed no relevant financial relationships.

Togas Tulandi

Department of Obstetrics and Gynecology, McGill University, 687 Pine Avenue West, Montreal, QC, H3A 1A1, Canada.

Disclosure: Togas Tulandi has disclosed no relevant financial relationships.

Aromatase inhibitors are traditionally used as an adjuvant treatment in postmenopausal women with estrogen receptor-positive breast cancer [1]. They work by decreasing the conversion of androgen to estrogen. Nononcologic use of aromatase inhibitors was pioneered by Mitwally and Casper in 2000 [2], who used them to induce ovulation. Many studies subsequently proved their efficacy. Owing to their ability to decrease estrogen, aromatase inhibitors have also been used for other estrogen-dependent conditions such as uterine myoma and endometriosis.

The purpose of this article is to review the use of aromatase inhibitors for a variety of gynecologic conditions.

Pharmacology of aromatase inhibitors

Aromatase is a microsomal enzyme of cytochrome p450 hemoprotein that catalyzes the conversion of androgens to estrogens. This enzyme works in many sites of the body including the ovaries, brain, placenta, adipose tissue, liver, bone and breast. Aromatase inhibitors cause to a decrease in estrogen concentration, which in turn lead to an increase in FSH secretion from the pituitary gland. Increased FSH levels subsequently stimulate follicle development.

To date, there have been three generations of aromatase inhibitors (Table 1). The first-generation inhibitor was glutethimide, which induces medical adrenalectomy. It has many side effects including lethargy, nausea and skin rash. The second-generation inhibitors, such as fadrozole and formestane, are more selective and have fewer side effects. However, they have to be administered intramuscularly. The third-generation inhibitors include one steroidal (examestane) and two nonsteroidal medications (letrozole and anastrazole). They are selective, reversible and potent, and are now commonly used in clinical practice.

Letrozole is absorbed rapidly after oral intake and secreted by the kidneys with a half-life of 45 h. The main side effects are related to hypoestrogenism, including hot flushes and bone mineral loss. Less common side effects are headache, back pain, leg cramps and arthralgia. However, most of these side effects occur with prolonged use in postmenopausal women. With shorter use, such as for ovulation regulation, the side effects have been minimal [3–6].

Ovarian stimulation

For over three decades, clomiphene citrate has been the only oral ovulation-inducing agent. Its efficacy is demonstrated in the 60–90% ovulation rate. However, the pregnancy rate is only 10–40%. This has been attributed to the antiestrogen effect of clomiphene in the endometrium and the cervical mucus [3,4,7].

Another class of drugs that has been used for a long time are the gonadotropins. They are more effective than clomiphene but are associated with higher rates of ovarian hyperstimulation and multiple pregnancies. In addition, they are expensive and should be administered intramuscularly or subcutaneously.

Letrozole

In the first study of ovulation induction, ten women with clomiphene-resistant polycystic ovarian syndrome (PCOS) were treated with letrozole [1]. Ovulation occurred in seven out of ten patients, two patients had a clinical pregnancy and one had a biochemical pregnancy. Subsequent studies confirmed the efficacy of letrozole as an ovulation-inducing substance [2–4].

It appears that letrozole is as effective as clomiphene citrate. In two quasi-randomized trials, the authors found that the ovulation and pregnancy rates of the two medications were similar [8,9]. In the first study by Bayar et al., 46 patients were randomized to receive either 2.5 mg of letrozole or 100 mg of clomiphene daily from day 3 to 7 of the menstrual cycle [8]. Endometrial thickness in the midcycle was similar in both groups. Ovulation and pregnancy rates in the letrozole group were 81 and 9%, respectively, and in the clomiphene group were 85 and 12%, respectively.

In the second study, 50 patients were randomized to receive letrozole with a starting dose of 2.5 mg and increasing by up to 5 mg daily, or clomiphene with starting dose of 50 mg and increasing by up to 100 mg daily from day 5 to 9 of the cycle [9]. The mean number of dominant follicles and the pregnancy rates in both groups were comparable. However, the endometrial thickness was thicker in the letrozole group (6.9 vs 5.9 mm).

In both studies, randomization was achieved by allocating one group of patients with odd numbers into the letrozole group and those with an even number into the clomiphene group. Both the physicians and the patients were not blinded, and these factors are potential biases.

In a nonblinded randomized trial, Badawy et al. evaluated 769 infertile women treated with 100 mg of clomiphene citrate (n = 420), 5 mg of letrozole (n = 269) or 1 mg of anastrazole (n = 107) [10]. Human chorionic gonadotropin was administered when the dominant follicle reached 18 mm. The control group was age-matched women who conceived spontaneously (n = 200). Pregnancy rates among all groups were comparable; 11.1% in letrozole group, 12.1% in clomiphene group, 10.5% in anastrozole group, and 7% in control group. The miscarriage rates were also similar.

In 2008, the American College of Obstetrics and Gynecology stated that letrozole may have a role in the treatment of clomiphene-resistant patients [11]. However, there is no evidence that it is more effective than clomiphene for ovulation induction. They concluded that the role of aromatase inhibitors in ovulation induction is being investigated. In any event, it appears that letrozole may have advantages over clomiphene citrate, including reduced rates of multiple pregnancies, reduced estradiol level and less of an antiestrogen effect on the endometrium.

Letrozole in women with PCOS

In a randomized trial in women with PCOS, Atay et al. reported favorable results with 2.5 mg letrozole over clomiphene 100 mg daily from day 3 to 7 of the cycle [11]. They found that the ovulation rate and the pregnancy rate in the letrozole group (82.4 and 21.6%, respectively) were significantly higher than in the clomiphene group (63.6 and 9.1%, respectively). The number of dominant follicles in the letrozole group (1.2) was lower than in the clomiphene group (2.4), while the endometrial thickness in the letrozole group was greater.

In another randomized study, 438 women with PCOS were randomized to receive 5 mg of letrozole or 100 mg of clomiphene daily for 5 days [12]. The total number of follicles was higher in the clomiphene group than in the letrozole group (6.8 ± 0.3 vs 4.4 ± 0.4). However, there were no differences in the ovulation rates (67.5% letrozole vs 70.9% clomiphene), the pregnancy rates per cycle (15.1% letrozole vs 17.9% clomiphene) and miscarriage rates (12.1 letrozole vs 9.7% clomiphene).

Clomiphene is still considered the first line of treatment of anovulation in women with PCOS. To date, letrozole is still an off-label medication for ovulation purposes [13]. Its use should be preceded by a thorough discussion with the patient regarding the risk and benefits.

When metformin was added to letrozole (2.5 mg/day) or clomiphene treatment (100 mg/day) in anovulatory women, one small single-blind randomized study reported a pregnancy rate of 34.5% in the letrozole–metformin group and 16.6% in the clomiphene–metformin group [14]. The full-term pregnancy rate was higher in the letrozole–metformin group.

Table 2 shows the ovulation rate, pregnancy rate and endometrial thickness in women treated with letrozole. Multiple pregnancies are almost nonexistent.

Letrozole in idiopathic infertility

Letrozole also appears beneficial in couples with unexplained infertility. Compared with clomiphene, it is associated with a higher pregnancy rate, lower estradiol levels, fewer follicles, thicker endometrium and better endometrial blood flow as observed on Doppler ultrasound [13]. Increasing the dose of letrozole to 7.5 mg appears to be unnecessary. Al-Fozan et al. randomized 154 women to receive 7.5 mg letrozole or 100 mg of clomiphene daily. The pregnancy rate was 11.5% in letrozole group and 8.9% in the clomiphene group. The miscarriage rate was higher in the clomiphene group [15].

Anastrazole

Another third-generation aromatase inhibitor is anastrozole. Al-Omari et al. compared the efficacy of letrozole versus anastrozole in 22 PCOS patients. The results were in favor of letrozole with a higher ovulatory rate (84.4 vs 60%) and pregnancy rate (27 vs 16.6%). The doses of letrozole and anastrozole were 2.5 mg/day for 5 days and 1 mg/day for 5 days, respectively. It is possible that the anastrazole dose was too low [16].

Letrozole & gonadotropin

The use of aromatase inhibitors in conjunction with gonadotropins is associated with a significant decrease in the gonadotropin requirement [17,18], with comparable pregnancy rates. This is despite thinner endometrium in the combined treatment than in the gonadotropin-only regime [19].

Letrozole in assisted reproductive technology

The role of aromatase inhibitors in assisted reproductive technologies remains to be seen. In 2004, Goswami et al. treated a group of nonresponder women with letrozole plus FSH or long gonadotropin-releasing hormone (GnRH) agonist protocols plus FSH. The letrozole group required a lower dose of gonadotropin and had lower estradiol levels. The clinical outcomes were comparable.

A similar result was reported by Schoolcraft et al.[20]. They randomized 534 poor responders to a GnRH agonist flare protocol or GnRH antagonist/letrozole protocol. The pregnancy rate in the letrozole group was lower than in the GnRH analogues (GnRHa) flare group (37 vs 52%). In another study among poor responders, the investigators reported that the addition of letrozole to FSH treatment led to a higher number of oocytes retrieved and a higher implantation rate [21]. The pregnancy rate in the combined group appeared to be higher, but it did not reach statistical significance.

Dose & duration of treatment with letrozole

Based on dosing for breast cancer treatment in postmenopausal women, letrozole is usually given in the dose of 2.5 mg from day 3 to 7 of the cycle. However, when the dose of 5 mg was compared with 2.5 mg, Al-Fadhli et al. found that the 5 mg dose was associated with a higher pregnancy rate (26.3 vs 5.9%) [22]. In another randomized trial, Badawy et al. reported that a 7.5 mg daily dose was associated with a higher number of follicles compared with the 2.5- or 5-mg dose [23]. However, the pregnancy rates were comparable.

Letrozole can also be given in a single dose (20 mg). In a small study, it was reported that the ovulation and pregnancy rates of the single dose were similar to the 5-day regime [24].

The ideal duration of the treatment is yet to be established. Badawy et al. randomized 218 women with PCOS to 5 mg of letrozole daily for 5 days (days 1–5) or 2.5 mg letrozole for 10 days (days 1–10). The pregnancy rate in the long protocol (17.4%) was significantly higher than in the short regime (12.4%) [25]; however, more studies are needed.

Safety

The safety of letrozole as an ovulation-inducing agent has been addressed by several groups [23–25]. Concerns regarding the safety of letrozole were raised at an abstract presentation at the 2005 American Society for Reproductive Medicine (ASRM) meeting [26]. As a result, Health Canada (ON, Canada) and Novartis Pharmaceuticals (QC, Canada) warned against using letrozole for ovulation induction [27]. This finding was challenged when the incidence of congenital anomalies was evaluated in a study of 911 babies born after fertility treatment with either letrozole or clomiphene.

Tulandi et al. reported that, compared with clomiphene, the rate of overall congenital malformations, major malformation rate and all congenital cardiac anomalies were lower in the letrozole group [28]. The fact that letrozole has a short half-life (45 h)ensures that the drug will be cleared completely from the body before implantation time. This puts the possibility of teratogenic effects resulting from medication in doubt. It seems that, compared with gonadotropin or letrozole, clomiphene was associated with a higher risk of neural tube defects and severe hypospadias [29].

Aromatase inhibitors for gynecologic conditions

There have been many studies evaluating the use of aromatase inhibitors in ovulation induction and regulation. Their use in other gynecologic conditions has not been widely addressed.

Fertility preservation

Owing to their ability to decrease estrogen concentration, aromatase inhibitors are especially useful in the induction of follicle development in women with estrogen-dependent neoplasia, such as breast cancer [30,31]. Oktay et al. used a combination of letrozole and gonadotropin in women with breast cancer for the purpose of oocyte or embryo cryopreservation [1]. A similar protocol could be used for young women with endometrial cancer undergoing fertility preservation [32].

Endometriosis

The main aim of endometriosis treatment is to deprive the endometriotic implant of estrogen [33,34]. There have been case reports demonstrating the efficacy of aromatase inhibitors in the treatment of severe endometriosis [35].

In a randomized study of comparative treatment of endometriosis with anastrazole/GnRH agonist or GnRHa alone, the authors found that the combined group was associated with a statistically significant decrease in estradiol level, longer pain-free time periods and decreased recurrence [36].

Myoma & adenomyosis

Myoma is another condition that is estrogen dependent [37]. Parsanezhad et al. randomized 70 women with single uterine myomas equal or more than 5 cm in size into two groups. The first group received 2.5 mg/day of letrozole and the second group was treated with triptorelin 3.75 mg/month for 12 weeks. The reduction in myoma size was higher in the letrozole group (45 vs 33.2%) [38].

Adenomyosis is another condition that could be treated medically with on aromatase inhibitor. In a case report, a combination of anastrazole and GnRHa was associated with a 60% reduction of uterine volume in 8 weeks and improvement in symptomatology [39].

Expert commentary

Aromatase inhibitors are a group of medications that act by blocking the aromatization of androgen to estrogen. Unlike clomiphene, they do not have an antiestrogen effect. This makes them ideal for ovulation induction and controlled ovarian hyperstimulation. They are fairly inexpensive, active orally and appear to be safe for the fetus. In addition, the risk of multiple pregnancies is almost nonexistent.

Owing to their property in decreasing estrogen concentration, aromatase inhibitors could also be used for estrogen-dependent conditions including endometriosis, myoma and adenomyosis. In addition, they could be useful for stimulation of follicle development in women with estrogen-dependent neoplasia who wish to preserve their fertility.

Five-year view

The risk of multiple pregnancies associated with ovulation induction or superovulation could be minimized with the increased use of aromatase inhibitors. More studies are needed to prove the value of assisted reproductive techniques. Whether longer duration of treatment leads to a better pregnancy rate remains to be seen. Compared with gonadotropins, the use of aromatase inhibitors is associated with a reduced estrogen concentration. Accordingly, they can be used for fertility preservation in women with estrogen-dependent cancer.

Aromatase inhibitors have a role in the treatment of estrogen-dependent conditions including endometriosis, myoma or adenomyosis. More studies are required to establish their place in the treatment of such disorders.

Table 1. Three generations of aromatase inhibitors.

Generation	Aromatase inhibitor
First generation	Aminoglutethimide
Second generation	Fadrozol Formestane
Third generation	Letrozole (nonsteroidal) Anastrazole (nonsteroidal) Examestane (steroidal)

Table 2. Rates of ovulation, pregnancy and multiple pregnancy, and endometrial thickness in women treated with letrozole.

Study (year)	Patients (n)	Ovulation rate (%)	Pregnancy rate (%)	Endometrial thickness (mm)	Multiple pregnancy	Ref.
Mitwally et al. (2001)	12	75	25	14.2	0	[2]
Bayar et al. (2006)	21	81	10	6.9	0	[8]
Atay et al. (2006)	51	82	21.6	8.4	0	[11]
Baruah et al. (2009)	25		19	6.9	Not stated	[9]

Key issues

• • Letrozole is the most commonly used aromatase inhibitor. It is selective, reversible and effective.

• • Aromatase inhibitors are effective for ovulation induction and superovulation. The results are comparable with those of clomiphene citrate, with a minimal risk of multiple pregnancies and they are not associated with the antiestrogen effect on the endometrium or the cervix.

• • The role of aromatase inhibitors in assisted reproductive technology needs further exploration.

• • Compared with clomiphene, letrozole seems to be associated with a lower risk of neural tube defects and severe hypospadias.

• • Aromatase inhibitors can be used for fertility preservation in women with estrogen-dependent neoplasias, including breast cancer.

• • Aromatase inhibitors can be used for the treatment of estrogen-dependent conditions such as endometriosis, myoma and adenomyosis.

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The use of aromatase inhibitors in infertility and gynecology

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1. A 28-year-old nulliparous woman with a history of polycystic ovarian syndrome (PCOS) and infertility presents. What should you consider before discussing the possibility of treatment with letrozole for her infertility?

• □ A Pregnancy rates associated with letrozole seem at least as high as those for clomiphene

• □ B Letrozole is associated with a high miscarriage rate

• □ C Letrozole is associated with a higher risk for multiple pregnancies compared with other fertility drugs

• □ D The addition of metformin to letrozole significantly reduces its efficacy in infertility treatment

2. What should you consider regarding the potential adverse effects associated with aromatase inhibitors?

• □ A Letrozole is associated with higher rates of neural tube defects only compared with clomiphene

• □ B Letrozole is associated with higher rates of severe hypospadias only compared with clomiphene

• □ C Letrozole is associated with higher rates of neural tube defects and severe hypospadias compared with clomiphene

• □ D Letrozole is associated with lower rates of neural tube defects and severe hypospadias compared with clomiphene

3. The patient from question 1 eventually requires ART. Which of the following statements best summarizes the role of aromatase inhibitors in ART?

• □ A Only letrozole appears to significantly improve pregnancy rates in ART

• □ B Only anastrazole appears to significantly improve pregnancy rates in ART

• □ C Letrozole significantly reduces the efficacy of FSH in promoting pregnancy

• □ D There is no established role for aromatase inhibitors in ART

4. The patient from question 1 has a successful pregnancy. You see her 10 years later for pelvic pain, and she is diagnosed with endometriosis and uterine myomas. What should you consider regarding the use of aromatase inhibitors for these conditions?

• □ A Adding anastrazole to a GnRH agonist will increase estradiol levels

• □ B Anastrazole may help prevent recurrence of endometriosis

• □ C Letrozole is less effective than GnRH agonists in reducing the size of myomas

• □ D Letrozole should not be added to GnRH agonists in the treatment of endometriosis or uterine myomas