Learning Objectives:After participating in this continuing education activity, the provider should be better able to:
1. Explain the mechanism of action of aromatase inhibitors, as it relates to the physiology of the hypothalamic-pituitary-ovarian axis.
2. Apply the current evidence regarding use of aromatase inhibitors in treatments of a number of gynecologic disorders.
3. Counsel patients regarding safety data and potential adverse effects of aromatase inhibitors.
Estrogen is one of the primary corticosteroid hormones for female physiology and reproduction. In reproductive-age women, estrogen is mainly produced in the ovary. However, the placenta, brain, adipose tissue, muscle, bone, and vascular tissue also produce it in varying amounts. Aromatase is the crucial enzyme involved in the conversion of androgens to estrogens, specifically the hydroxylation of a 19-carbon androgen to an 18-carbon estrogen. There are 3 sequential hydroxylation steps in this complex reaction that result in the creation of estradiol. It is a cytochrome P450 enzyme which is located on the endoplasmic reticulum of estrogen-producing cells.1
The pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the anterior pituitary to synthesize and secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (Figure 1A). In the early follicular phase of the menstrual cycle, LH binds to theca cells of the ovary, which enhances sequestration of cholesterol and its subsequent conversion to androgens such as androstenedione and testosterone. These corticosteroids then move across to the granulosa cells where aromatase, stimulated by FSH, converts the androstenedione to estrone and, to a lesser extent, testosterone to estradiol.2 Subsequently, estrone is converted to estradiol by 17-[beta] hydroxysteroid dehydrogenase (Figure 2). The conversion of androgens to estrogens is called aromatization and is inhibited by aromatase inhibitors.
Aromatase inhibitors have 2 primary mechanisms of action. First, they reduce estradiol levels, which in turn blocks estradiol's impact on estrogen-sensitive end organs. Second, a reduction of estradiol levels decreases the feedback inhibition of the hypothalamic-pituitary-ovarian (HPO) axis, leading to an increase in GnRH secretion and therefore an increase in pituitary gonadotropins (Figure 1B).
This article reviews a variety of potential uses of aromatase inhibitors in the field of gynecology. It is important for obstetricians/gynecologists to understand the current evidence around their use and apply it toward potential treatment options for their patients.
Current Status of Aromatase Inhibitors
Three aromatase inhibitors are currently available in the United States. Letrozole and anastrozole are reversible aromatase inhibitors that compete with androgens for aromatase binding sites. These restrict estrogen by 97% to 99% at doses of 1 to 5 mg.3 Exemestane is a corticosteroid-derived aromatase inhibitor that binds irreversibly to aromatase and permanently inactivates the enzyme. All 3 aromatase inhibitors seem to have similar clinical efficacy.4
Significant reduction of estrogen in peripheral circulation by the aromatase inhibitors has been promising in the treatment of estrogen-dependent diseases in gynecology practice. Currently, all 3 aromatase inhibitors are FDA-approved for postmenopausal estrogen receptor positive (ER+) breast cancer.
Therapeutic Uses
ER+ Postmenopausal Breast Cancer
Aromatase inhibitors are FDA-indicated for adjuvant therapy in ER+ postmenopausal breast cancer patients. The large clinical trial focusing on the use of aromatase inhibitors in breast cancer patients with resectable, ER+ tumors, known as the Arimidex, Tamoxifen, Alone, or in Combination (ATAC) trial, compared anastrozole (an aromatase inhibitor) alone either with tamoxifen (a selective estrogen receptor modulator) alone or with a combination of the 2, as adjuvant treatment in women with early breast cancer after surgical resection. Anastrozole was compared with tamoxifen for 5 years in 9366 postmenopausal women with localized breast cancer, and anastrozole was associated with significantly prolonged disease-free survival and time-to-recurrence, and significantly reduced distant metastases and contralateral breast cancers as compared with tamoxifen. The initial data analysis at 3 years revealed that the combination treatment arm outcomes were not significantly different from tamoxifen-only outcomes and were significantly worse than anastrozole-only alone; therefore, the combination treatment arm was closed due to low efficacy.5
Another important aspect of letrozole use in this patient population is length of adjuvant treatment. In another double-blind, placebo-controlled trial conducted to assess the effect of extending use of letrozole from 5 to 10 years, patients were randomized to either letrozole 2.5 mg or placebo. The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. The study concluded that it was safe and beneficial for postmenopausal patients with hormone receptor-positive breast cancer to take an aromatase inhibitor as adjuvant therapy for 5 additional years after initial treatment.6
Ovulation Induction in Polycystic Ovarian Syndrome
Anovulatory cycle in patients with polycystic ovarian syndrome (PCOS) is a common cause of infertility. Aromatase inhibitors have been promoted as ovulation induction agents for patients with PCOS, given lack of estrogen-negative feedback and increase in gonadotropin secretion to stimulate follicular growth. Because aromatase inhibitors do not deplete estrogen receptors like clomiphene citrate (CC), normal central feedback mechanisms remain intact. As the dominant follicle grows and estrogen levels rise, normal negative feedback occurs centrally, resulting in subsequent suppression of FSH and atresia of the smaller follicles, creating in most cases a single dominant follicle and mono-ovulation.7 Mitwally et al8 conducted multiple studies evaluating pregnancy outcomes after use of aromatase inhibitors for ovulation induction. In a 2005 study, pregnancy rates were compared among various treatments including letrozole, CC, and gonadotropins. Letrozole was noted to have higher pregnancy rates per cycle compared with CC and gonadotropin use. Pregnancies conceived with letrozole treatments were associated with similar miscarriage and ectopic pregnancy rates compared with all other groups, but letrozole use was associated with a significantly lower rate of multiple gestations.8
The Reproductive Medicine Network (RMN), a multicenter research group sponsored by the National Institutes of Health, published the Pregnancy in Polycystic Ovary Syndrome (PPCOS I) study in 2007, in which CC was found to be 3 times more effective than metformin at achieving live birth; no additional benefit was noted when CC and metformin were combined. However, the PPCOS I trial also highlighted the limitations of CC and the need for better ovulation induction agents given a relatively low success rate. Only 23% had a live birth in the CC group of the PPCOS trial and a further 25% never had a single documented ovulation during the study period. There was also concern about multiple pregnancies (4%-6% multiple pregnancy rate with one triplet gestation in the CC containing arms), and possible adverse effects of CC (ie, ovarian hyperstimulation syndrome).9
In a follow-up study known as the PPCOS II trial, the RMN conducted a large, randomized, double-blinded study comparing letrozole with CC in women with PCOS. Women were randomized to 2 different treatment arms, either CC 50 mg daily for 5 days or letrozole 2.5 mg daily for 5 days (days 3-7 of cycle) for a total of 5 cycles, with iteratively increased doses of both drugs in subsequent cycles for poor ovulatory response. In this study, letrozole seemed to be superior to CC in terms of live birth, with letrozole having a 27.5% live birth rate after 5 cycles versus CC having a 19.2% live birth rate. There were no differences found in singleton and twin rates, and no triplets occurred at all in the study. The pregnancy loss rates between the 2 arms of the study were also comparable. Overall, ovulation itself seemed to be more prevalent in the letrozole arm as well.10 In large part due to the result of this trial, letrozole is now commonly used as first-line therapy for ovulation induction for women with PCOS.
Endometriosis
Endometriosis is a common, estrogen-dependent disease characterized by ectopic endometrial glands and stroma. Medical treatment of the disease strives to create a hypoestrogenic or pseudomenopause state leading to suppression of endometriotic tissue. Recent work has shown substantial impact of letrozole in reducing endometriosis-related pelvic pain. A systematic review of 8 studies that included a total of 137 patients showed that aromatase inhibitors combined with progestogens, oral contraceptive pills, or GnRH agonists all reduced mean pain scores, reduced lesion size, and improved quality of life in patients with endometriosis.11
Another small, uncontrolled trial of 8 women sought to assess whether endometriomas could be reduced in size. This study offered baseline ultrasound evaluation to determine presence of an endometrioma followed by a 3-month exposure to letrozole 5 mg and norethindrone 5 mg with subsequent repeat ultrasound. (The norethindrone was given for bone protection in the setting of profoundly decreased levels of estradiol, as was seen with the letrozole.) Fourteen endometriomas were included in the assessment. There was a significant reduction in diameter of 50% and reduction in volume of 75% in the patients studied. In addition, all of the patients experienced significant pain scale improvements.12
A similar small trial was conducted for 10 women with prior surgical and medical treatments for endometriosis and unsatisfactory results. In this study, patients had a laparoscopy with biopsies of endometrial implants 1 month before the start of the therapy. Next, letrozole 2.5 mg with norethindrone 2.5 mg was given daily for 6 months, and patients were subsequently evaluated with a second-look laparoscopy at the conclusion of the 6 months. The second-look laparoscopy showed complete resolution of endometriotic implants. In addition, the average pain score decreased significantly in all but one of the cases.13 Although these observational studies suggest significant potential benefits of aromatase inhibitors for treatment of endometriosis, more powerful, randomized controlled trials are needed to support these findings.
Male Obesity and Infertility
In the PPCOS II trial, women with the lowest body mass index (BMI) had the highest pregnancy rates regardless of treatment given and the benefit were inversely related to female patient weight. Although the impact of obesity on the female is well-known, less is known about the impact of obesity for the male partner. In a study of over 1500 Danish men, BMI was associated with diminished semen quality and reproductive hormones. Increased BMI was associated with decreased serum testosterone, sex hormone binding globulin, inhibin B, and increased estradiol. It is speculated that elevated estradiol, likely a result of peripheral aromatization in adipose tissue, reduces gonadotropin secretion due to negative feedback centrally, which in turn may decrease sperm production.14
This potential mechanism is further supported by the observation that treatment of obese men with testolactone and letrozole was associated with a reversal of this idiopathic hypogonadotropic hypogonadism. In one study, 1-g testolactone (a first-generation, relatively nonspecific aromatase inhibitor) was given to 6 obese men daily for 6 weeks, with significant improvements in serum testosterone levels, serum LH levels, and decreased serum estradiol levels.15 In a second study, letrozole was given to 10 obese men for 6 weeks in doses between 7.5 and 17.5 mg daily, with similar improvements in LH, FSH, testosterone, and decreased estradiol.16 This relationship has been shown in both oligo- and azoospermic men.17 Interestingly, CC has also been used for treatment in hypogonadal infertile men, and in one small study had a greater impact on improving serum hormone levels, including total testosterone and the testosterone-estradiol ratio, as compared with aromatase inhibitors.18 Given the lack of randomized, controlled trials, it remains unclear whether improvements in hormonal markers and sperm parameters translate into improved pregnancy and live birth rates. Additionally, whether it is high estrogen alone, decreased androgens, or an increased estrogen-testosterone ratio, which leads to the compromised sperm production, remains unknown.
Leiomyomata
Uterine leiomyomata, or fibroids, are the most common benign tumors in reproductive-age women. Aromatase is overexpressed in leiomyoma tissue through signaling pathways at the transcriptional level, which enhances local estradiol production and may be associated with rapid and pathologic growth of the fibroids.19 Therefore, aromatase inhibitors may play a role in the conservative treatment of leiomyomas.
In a prospective study evaluating the effect of anastrozole on symptomatic uterine leiomyomata, 41 patients who had known fibroids were treated with anastrozole in an intent to treat protocol over 3 months with a 55% reduction in the myoma volume. In addition, the patients also had improved menstrual symptoms including a significant increase in hematocrit from 33.4% to 37.2% (P < 0.001).20 In a separate prospective study in which 20 premenopausal women were treated with anastrozole, there was an average reduction of 9.32% in uterine volume, with a maximum up to 32% reduction in perimenopausal women over a 3-month period. Reduction of symptoms of uterine leiomyoma, including menstrual volume, duration of menstruation, and dysmenorrhea, was also seen.21
Another randomized, controlled clinical trial compared the use of letrozole versus GnRH agonist (GnRHa), specifically triptorelin, in 70 patients, evaluating fibroid volume after 12 weeks of treatment. Leiomyoma volume measured by transvaginal ultrasound and serum hormone levels (estradiol, testosterone, and gonadotropins) were assessed at baseline and during treatment at weeks 2, 4, 6, and 12. Study results showed an average reduction of 45.6% in myoma volume in the letrozole group and 33.2% in the triptorelin group. There were no statistically significant differences between the 2 groups in myoma volume decrease. Side effects in the triptorelin group, principally hot flashes, were significantly more common, with 96.3% of patients in the GnRHa group reporting vasomotor symptoms but none in the letrozole group. This is consistent with the initial rise of estradiol levels noted after 2 weeks in the triptorelin group, whereas there was no initial rise noted in the letrozole group. The study concluded that avoidance of the initial flare-up with aromatase inhibitor may be advantageous for women in the management of uterine leiomyomas.22
Adenomyosis
Patients with adenomyosis have changes in the uterine architecture with varying degrees of symptoms, and the classic treatment has been surgical management with hysterectomy. Diagnosis is made via hysterectomy specimen pathology, although MRI has been shown to be very sensitive in evaluation of the junctional zone between the endometrium and the myometrium. Although surgical treatment was previously the norm, attempts have been made to hormonally and medically control the disease and data suggest aromatase inhibitors may play a role.
Given that GnRH agonists were the medical treatment of choice in patients with adenomyosis, a prospective randomized trial from Egypt compared GnRH agonist and letrozole use. A total of 16 patients in each of 2 arms of the study were recruited. Parenthetically, 2 patients became pregnant in the letrozole arm. There were no significant differences in the total uterine size between the 2 groups over the course of 12 weeks, and there was a substantial decrease in both groups' volume from baseline. In addition, there was almost complete eradication of the patients' symptoms. The study concluded that aromatase inhibitors are as effective as GnRH agonists in reducing uterine, adenomyosis, adenomyoma volume, and symptoms, and given the relative cost-effectiveness of the treatment a recommendation was made to treat these patients with aromatase inhibitors rather than GnRH agonist.23
A 2007 case report in Fertility and Sterility highlighted an additional approach to adenomyosis treatment. A 34-year-old patient with severe adenomyosis and anemia despite treatment with GnRH agonist was then managed with GnRH agonist and concomitant letrozole. The reduction in uterine volume was approximately 60% after 45 days of treatment and the abnormal uterine bleeding stopped after 30 days of concomitant treatment. Interestingly, the patient subsequently chose to discontinue the letrozole and remain on the GnRH agonist and despite discontinuation of the letrozole she continued to experience improved symptoms compared to prior. The authors suggest that aromatase inhibitors might have changed the microscopic nature of the adenomyotic tissue in view of the observation that she had no recurrence of uterine bleeding and no further reduction of uterine size over the 6 months after cessation of letrozole.24 Overall, observational research suggests the utility of aromatase inhibitors as a single or adjunct agent in the conservative treatment of adenomyosis, thereby allowing the patient to avoid hysterectomy and retaining potential fertility. Of course, more randomized, controlled trials are needed.
ER+ Breast Cancer and Oncofertility
Women with ER+ breast cancer may potentially be harmed by going through an in vitro fertilization (IVF) cycle where estradiol levels are one or more orders of magnitude higher than in a typical ovulatory natural cycle. By keeping estradiol levels low, nascent tumor cells would not be stimulated. In a prospective, controlled clinical trial, Oktay et al25 compared the use of tamoxifen alone or letrozole combined with low-dose FSH in women with breast cancer who desired embryo cryopreservation. The combination therapy was associated with lower peak estradiol levels and a higher number of embryos. The cancer recurrence rate was similar between the stimulated and control groups.25 Another study comparing letrozole versus gonadotropin use in patients with ER+ breast cancer who wished to cryopreserve their oocytes also found significantly lower estradiol levels in the letrozole group. The study also reported a statistically significant lower yield of oocytes available for cryopreservation in the letrozole group (6.6 vs 8, P = 0.038). However, this may be clinically of lesser significance if it could impact patient survival.26
Ultimately, little data exist regarding the long-term safety profiles of stimulation methods for IVF cycles in patients with ER+ cancers. A case report from China describes a patient with a history of ER+ breast cancer who underwent IVF with letrozole suppression and ultimately had a successful twin delivery.27 The available data thus far suggest lower estradiol levels, a safety issue that has traditionally been considered advantageous in the case of ER+ cancers, without compromising egg number and quality.
Safety Data and Potential Adverse Effects
Adverse events that may be associated with aromatase inhibitors are due to hypoestrogenemia. Side effects include hot flashes, vaginal dryness, arthralgias, decreased bone mineral density, and an increased fracture rate. To mitigate symptoms of vaginal dryness, first-line treatment recommendations include nonhormonal treatments, such as vaginal moisturizers. A case-control study of women with breast cancer who used vaginal estrogen did not show an increase in recurrence with local estrogen use; therefore, vaginal estrogen may also be considered as a treatment option in symptomatic women.28 When compared with tamoxifen, aromatase inhibitors are associated with reduced risk of thrombosis, endometrial cancer, and abnormal vaginal bleeding.29
Long-term aromatase inhibitor use and resultant estrogen deficiency are associated with risk of osteoporosis. The National Comprehensive Cancer Network recommends baseline and periodic follow-up bone density testing for women with breast cancer treated with aromatase inhibitors.30 In the ATAC trial, after a median follow-up of 100 months, patients receiving anastrozole alone had a significantly higher fracture incidence compared with those receiving tamoxifen alone (2.93% for anastrozole vs 1.90% for tamoxifen; P < 0.0001). However, the pronounced difference in annual fracture incidence rates observed during therapy did not persist beyond the 5-year treatment period, suggesting that aromatase inhibitor-related fracture rates decrease after treatment completion.31
Oral bisphosphonates have been shown to mitigate the bone loss effects of aromatase inhibitors. One trial examined the effects of oral bisphosphonates in patients receiving anastrozole therapy. Patients with a low-risk T score (>-1) received no intervention; patients with a T score less than -2 received oral risedronate; and patients with a T score between -1 and -2 were randomized to risedronate or placebo. For patients at low risk, bone loss during short-term follow-up was minimal. After 12 months, patients receiving anastrozole plus risedronate had a significant increase of 1.7% and 1.3% from baseline bone mineral density in their lumbar spine and hip, respectively, compared with anastrozole alone.32
Conclusion
The use of aromatase inhibitors has been studied for many years, and it is important for obstetricians/gynecologists to understand the current evidence surrounding their variety of uses. Aromatase inhibitors are currently FDA-approved for adjuvant treatment of postmenopausal receptor-positive breast cancer, and they are used as first-line agents for ovulation induction in patients with PCOS. There are strong data to support aromatase inhibitor use in the treatment of endometriosis given the effects of estradiol suppression. Promising data are available to suggest that aromatase inhibitors may be useful in the treatment of male obesity and infertility, leiomyomas, and adenomyosis. Aromatase inhibitors have also been used in controlled ovarian stimulation for patients with ER+ tumors desiring oocyte cryopreservation, allowing for good follicular response without the adverse impact of high estrogen levels.
Practice Pearls
* Aromatase is involved in the conversion of androgens to estrogens, and aromatase inhibitors cause decreased estradiol levels and decreased feedback inhibition of the HPO axis, ultimately leading to an increase in pituitary gonadotropins.
* Aromatase inhibitors are currently FDA-approved for adjuvant treatment of postmenopausal receptor-positive breast cancer.
* Aromatase inhibitors are used as first-line therapy for ovulation induction in women with PCOS.
* Aromatase inhibitors have also been evaluated and have shown promise in the treatment of endometriosis, male obesity and infertility, leiomyomas, adenomyosis, and oncofertility for patients with ER+ tumors.
* Aromatase inhibitors are generally well-tolerated. Adverse effects of aromatase inhibitors are related to effects of lack of estrogen (ie, hot flashes, vaginal dryness, and long-term use can be associated with osteoporosis and increased risk of bone fractures).
REFERENCES