Using aromatase inhibitors to induce ovulation in breast Ca survivors

By Mohamed F. Mitwally, MD, PhD, and Robert F. Casper, MD

The second installment in our two-part article on AIs looks at these agents as potential alternatives to clomiphene citrate and gonadotropins for stimulating fertility in breast cancer survivors.

Aromatase inhibitors — which block estrogen synthesis and lower estrogen levels throughout the body — are best known for their emerging role in treating breast cancer and preventing its recurrence after tamoxifen therapy (see "Preventing breast Ca with aromatase inhibitors," December 2003 issue). But equally exciting is the possibility that AIs may offer breast cancer survivors a safer alternative to ovulation induction. For the growing population of young breast cancer survivors — three of every 20 women diagnosed with this disease are younger than 45 — this is obviously good news.

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The diverse applications of breast cancer prevention and ovulation induction are not as far afield as they might seem, given the role estrogen plays in the development of a wide range of reproductive disorders. To review the basics, aromatase — which catalyzes the conversion of androstenedione and testosterone to estrone and estradiol respectively — is present in the ovaries, brain, adipose tissue, muscle, liver, breast tissue, and in malignant breast tumors. The main sources of circulating estrogens are the ovaries in premenopausal women and adipose tissue in postmenopausal women.¹

As we noted in Part I, AIs can be classified as steroidal or nonsteroidal and reversible (ionic-binding) or irreversible (suicide inhibitor, covalent binding). They're also classified by generation, with the most successful selective third-generation AIs anastrozole (Arimidex) and letrozole (Femara) used primarily to treat postmenopausal breast cancer. Third-generation oral AIs are extremely potent in inhibiting aromatase without significantly inhibiting other steroidogenesis enzymes (lowering estrogen levels by 97% to more than 99%). Other advantages are that these antifungal triazole derivatives are reversible, completely absorbed, and are rapidly cleared from the body. Despite some concerns about whether long-term use would raise the risk of osteoporosis and adverse cardiovascular events, adverse effects like hot flashes are milder.²

Currently, the two main medications used for ovulation induction (OI) are oral clomiphene citrate (CC) and injectable gonadotropins, chiefly recombinant follicle-stimulating hormone (FSH).^3-6 However, these drugs have their drawbacks — including the risk of life-threatening ovarian hyperstimulation syndrome and ovarian malignancy (Table 1). Our goal here is to look at the development of AIs as a new low-cost oral method of ovulation induction that could eliminate many of the problems of the current agents and improve the safety of infertility treatment in female breast cancer survivors.

 

TABLE 1 Disadvantages of current ovulation induction drugs Known risks and problems Risk of life-threatening ovarian hyperstimulation syndrome (mainly with gonadotropin injections) Multiple gestation Lower pregnancy rate despite high ovulatory rate (especially for CC) Intense monitoring required (especially with gonadotropin injections) High expense (gonadotropin injections) Parenteral administration (gonadotropin injections) Debatable risks and problems Poor obstetric outcome Risk of ovarian malignancy CC—clomiphene citrate

Why an alternative to clomiphene citrate is needed

Indisputably, clomiphene is a potent drug, inducing ovulation in 57% to 91% of patients. The pregnancy rate, on the other hand, is only between 20% and 40%.^5-9 The discrepancy may be due to CC's peripheral antiestrogenic effect, particularly at the level of the cervical mucus and endometrium.^12-17 The zu-isomer of CC (due to its long half-life of several weeks) accumulates in the body, adding to the persistence of the antiestrogenic effect.¹⁸ Another plausible explanation for the poor outcome of CC treatment is that it slows down uterine blood flow during the early luteal phase and the peri-implantation stage.¹⁹

CC's effect on the endometrium, believed to be one of the most important targets of the drug's antiestrogenic effect, may explain a large part of the lower pregnancy rate. Successful implantation requires a receptive endometrium, with synchronous development of glands and stroma.^20,21 Most studies of CC's effect on the endometrium have produced conflicting results, perhaps due to the different methodology used for endometrial assessment.^15-17,22-25

A recent prospective study, however, used morphometric analysis of the endometrium (a quantitative and objective technique to study CC's effect on the uterine lining) in a group of normal women. CC had a deleterious effect on the endometrium, reducing glandular density and increasing the number of vacuolated cells.²⁵ In addition, several investigators have confirmed reduced endometrial thickness — below the level thought to sustain implantation — in up to 30% of women receiving CC for OI or for unexplained infertility.^15-17 In light of these adverse antiestrogenic effects — as well as several unsuccessful approaches that have been tried to improve pregnancy rates with CC, such as combining it with tamoxifen (Table 2) — we attempted to use AIs as a new alternative to CC.^25-31

 

TABLE 2 Three unsuccessful approaches to improving pregnancy rates with CC Administering estrogen concomitantly during clomiphene citrate treatment26-28 Administering CC earlier in the menstrual cycle—on day 1 to 3 rather than day 5 29 Combining another selective estrogen receptor modulator such as tamoxifen, which has more estrogen agonistic effect on the endometrium, with CC or using tamoxifen as an alternative to CC30,31

Trying to decipher mechanism of action

In the late 1990s, we explored the possibility of mimicking CC's action without depleting estrogen receptors (ER), by administering an AI in the early part of the menstrual cycle. We hypothesized that blocking estrogen production from all sources by inhibiting aromatization would release the hypothalamic/pituitary axis from estrogenic negative feedback, thereby increasing gonadotropin secretion and thus stimulating ovarian follicles. Compared to CC, selective nonsteroidal AIs like letrozole have a relatively short half-life (roughly 45 hours) and seem ideal for this purpose, since they're rapidly eliminated from the body.^32,33 In addition, we expected no adverse effects on estrogen target tissues, since no ER downregulation occurs, in contrast to the ER depletion observed in CC-treated cycles.

Women with PCOS have a relative oversuppression of FSH, which may result from excessive ovarian-produced androgen being converted to estrogen by aromatization in the brain. The AIs suppress estrogen production not only in the ovaries — but also in the brain. In the case of PCOS, therefore, AIs should significantly increase the release of FSH and subsequent follicle stimulation and ovulation. We speculate that the actual FSH release is likely blunted by the high levels of circulating inhibin found in PCOS patients that would be unaffected by aromatase inhibition.^34-36 In addition, because aromatase inhibition doesn't antagonize ERs in the brain, the initiation of follicle growth produces increasing concentrations of both estradiol and inhibin.^37,38 These higher levels would result then in a normal secondary feedback loop that limits FSH response to aromatase inhibition, thereby avoiding the risk of high multiple ovulation and ovarian hyperstimulation syndrome (OHSS).

We later developed a second hypothesis to explain another of AIs' mechanisms of action in ovarian stimulation — one based on our belief that AIs also act locally in the ovary to make follicles more sensitive to FSH. This may result from the accumulation of intraovarian androgens, since inhibiting aromatase blocks the androgen substrate from being converted to estrogen.

It turns out that recent data do support a stimulatory role for androgens in early follicular growth in primates.⁵⁵ The findings by researchers that testosterone augments follicular FSH receptor expression in primates suggests that androgens indirectly promote follicular growth and the biosynthesis of estrogen by amplifying the effects of FSH.^39,40 In addition, a build-up of androgen in the follicle may stimulate insulin-like growth factor I (IGF-I), along with other endocrine and paracrine factors; this in turn may synergize with FSH to promote folliculogenesis.^41-44

It's likely that women with PCOS already have a relative aromatase deficiency in their ovaries, causing higher levels of intraovarian androgens.^45,46 And the higher levels probably lead to the many small follicles responsible for the polycystic morphology in their ovaries. Intraovarian androgens, as described above, might also increase the number of FSH receptors, making these PCOS ovaries exquisitely sensitive to a rise in FSH. One source of FSH is through the exogenous administration of gonadotropins (hence the high risk of OHSS). The other would be through endogenous increases in FSH as a result of reduced central estrogen feedback, thanks to aromatase inhibition. In the latter case, we speculate that a relatively small rise in FSH (because of the normal inhibin/estrogen feedback loop described previously) leads to single- or low-multiple follicle development, thus preventing OHSS.

AI's role in ovulation induction and controlled ovarian stimulation

Recently, we successfully used an AI to induce ovulation in women with PCOS and to augment ovulation in women with anovulatory infertility (unexplained- and endometriosis-related infertility).^47-49 We've subsequently examined the possibility of using an AI in conjunction with FSH injections to increase the number of preovulatory follicles that develop and to improve treatment outcome. Figure 1 summarizes our pregnancy rates with various OI regimens in 2,613 treatment cycles for intrauterine insemination or timed intercourse. We've shown that an AI (the third-generation drug letrozole) together with FSH significantly reduced the dose of FSH required to achieve an optimum ovarian stimulation.^50-52

We also reported — and others have subsequently confirmed — a significant increase in the development of preovulatory follicles when using the two drugs together in women who are poor responders.^53-62 In addition, using an AI during ovarian stimulation may improve treatment outcome by reducing the supraphysiologic estrogen levels attained when the multiple ovarian follicles were formed. Clearly, such a result could have obvious direct benefits for breast cancer survivors (see below). Table 3 summarizes the reported and potential future applications of AIs for ovarian stimulation, while Table 4 lists its advantages.

 

TABLE 3 Applications of AIs for ovarian stimulation Reported applications Ovulation induction in anovulatory women (for example, PCOS) Augmentation of ovulation in ovulatory infertility (unexplained, endometriosis-related and male-factor infertility) Controlled ovarian hyperstimulation alone or in conjunction with injectable gonadotropins Decreased cost of controlled ovarian hyperstimulation achieved by lowering the dose of injectable gonadotropins required for optimum ovarian stimulation Improved response to ovarian stimulation in poor responders Potential future applications Use with FSH and GnRH antagonists for controlled ovarian hyperstimulation Improvement in implantation rates Reduction of risk of severe ovarian hyperstimulation syndrome Prevention of endogenous premature LH surge In vitro maturation

 

TABLE 4 Advantages of AIs for ovulation induction High pregnancy rates Monofollicular ovulation in most of the patients with anovulation Reduced rate of multiple pregnancy Reduced risk of severe ovarian hyperstimulation syndrome Low cost of treatment (average $30–$100 per cycle) Convenience of administration oral route, different regimens including single-dose regimen

Adverse effects. Nonsteroidal AIs are generally well tolerated and the main adverse events were hot flushes and GI events, like nausea and vomiting, and leg cramps. Overall, very few patients withdrew from first- or second-line comparative Phase III trials because of drug-related adverse events.^63,64 The adverse effects that did occur were in older women with advanced breast cancer who were given the AIs on a daily basis over several months — a far different patient group from the usually healthy reproductive-aged women taking an AI for a short period for OI. We might expect AIs to be even safer, therefore, in younger women.

Effect on pregnancy outcome. Our preliminary data on pregnancy outcome after the use of AIs for ovarian stimulation supports the safety of these drugs. Table 5 shows the outcome of cycles in which women became pregnant after treatment with letrozole (alone or with FSH), with pregnancy cycles after CC treatment (alone or with FSH) and FSH treatment, and in spontaneous pregnancies (no ovarian stimulation) between 1999 and 2001 in Toronto.⁶⁵ Figure 1 shows the overall pregnancy rates when an AI was used for ovarian stimulation.

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Preserving fertility and inducing ovulation in breast Ca survivors

Breast cancer is the most common malignancy in reproductive- aged women. Of the more than 180,000 new cases each year in the United States, 25% occur before menopause and 15% in women younger than 45.^66-68 Although breast cancers in younger, premenopausal women are more likely to have a poorer prognosis, better treatments by multidisciplinary teams in specialist centers have improved survival rates.^69,70

Most women with breast cancer receive a combination of surgical treatment followed 4 to 6 weeks later by chemotherapy with cyclophosphamide and other drugs.^71,72 Cyclophosphamide is an alkylating agent that's known to adversely affect reproduction by inducing programmed cell death and apoptosis of ovarian follicles. Both a woman's age and the number of courses of chemotherapy she's undergone affect her risk of ovarian failure.⁷³ The likelihood of immediate ovarian failure increases with age, and each course of chemotherapy will significantly diminish ovarian reserve.^73,74 Even those women who do not immediately develop ovarian failure and become menopausal following chemotherapy are likely to experience infertility and early menopause.^75,76

Drawbacks of fertility preservation options. Most fertility preservation options for cancer survivors — like ovarian tissue cryopreservation and transplantation, as well as oocyte cryopreservation — are experimental. Ovarian cryopreservation and heterotopic transplantation have reportedly restored ovarian endocrine function in cancer patients, but no human pregnancies have occurred.^77-79 The technique of oocyte cryopreservation has a somewhat better track record — having resulted in successful pregnancies — but is rather inefficient.^80-82

Embryo cryopreservation — an established clinical technique to store excess embryos during in vitro fertilization treatment — has also been tried to preserve fertility in cancer patients.⁸³ However, IVF for the production of embryos might be associated with a major risk: The high levels of estrogen associated with the ovarian stimulation regimens currently used for assisted reproduction techniques can cause breast cancer cells to proliferate and disseminate.^84,85 Obviously, ovarian stimulation is needed to obtain many oocytes, and hence generate several embryos that can be frozen and later transferred to increase the chance of success in achieving a pregnancy. But many oncologists consider ovarian stimulation a strict contraindication for breast cancer survivors, mainly due to the high estrogen levels associated with the procedure.

To avoid those high estrogen levels, oocyte retrieval and embryo freezing have been tried during unstimulated (natural) cycles in these patients. A major problem with this option, however, is that most of the time you obtain only a single embryo.⁸⁶ Because pregnancy rates increase in direct proportion to the number of embryos obtained and transferred, increasing the number of stored embryos will increase the chance of future pregnancy after cryopreservation.⁸⁷ Moreover, obtaining multiple embryos might allow these patients to become pregnant more than once.

How soon to attempt pregnancy after breast Ca. There are no hard and fast rules — nor sufficient data to clarify — when a breast cancer survivor should start trying to get pregnant. Many experts recommend postponing pregnancy for at least a 2- to 5-year recurrence-free interval after breast cancer diagnosis and treatment.^88-90 However, the real challenge is that by the time 2 to 5 years have gone by, many more women who didn't experience ovarian failure and menopause immediately after chemotherapy will become infertile due to a significant decrease in ovarian reserve. With the growing awareness of the adverse effects of breast cancer chemotherapy on reproduction, coupled with a greater number of reproductive-aged women who survive breast cancer due to early diagnosis and treatment, many patients are looking for safe and valid methods to conceive.

Reviewing the literature about pregnancy after breast cancer, researchers concluded that the effect of a subsequent pregnancy on patients who've had breast cancer is difficult to interpret due to differing populations and differing data collection techniques.⁹¹ They recommended that until adequate data are available, advice to women regarding subsequent pregnancy has to be made on a patient-by-patient basis.

SERMs for ovulation induction. Recently, Oktay and colleagues tried tamoxifen for multiple follicle stimulation for IVF in 12 women with previously treated breast cancer at a dose of 40 to 60 mg for about 7 days beginning on days 2 and 3 of the menstrual cycle.⁹² Patients underwent 15 IVF cycles, with fresh embryo transfer in six cycles, and cryopreservation in nine cycles. The investigators compared the results with a retrospective control group that included five natural-cycle IVF attempts.

They found that cycle cancellation occurred significantly less often in tamoxifen IVF cycles (1/15 vs. 4/9) — and also that tamoxifen IVF cycles produced a greater number of mature oocytes (1.6 ± 0.3 vs. 0.7 ± 0.2) and embryos (1.6 ± 0.3 vs. 0.6 ± 0.2, P=0.02) per initiated cycle. The authors concluded that tamoxifen stimulation may provide a safe method of IVF and fertility preservation for breast cancer patients.

However, when tamoxifen is used to stimulate the development of multiple ovarian follicles, high estrogen levels remain a problem — despite the drug's anti-ER effect. In fact, with both tamoxifen and CC, supraphysiologic levels of estrogen occur because of central ER depletion and the loss of estrogen negative feedback on gonadotropins. We have demonstrated estradiol levels as high as 1,000 pmol/L per mature follicle with CC treatment.^47,48 In addition, both tamoxifen and CC may directly damage the endometrium, which in turn could reduce the chance of successful implantation in patients undergoing ovarian stimulation for ART.^59-62,74,75

Conclusions

Our preliminary studies, and those of others, show that AIs are effective for inducing or augmenting ovulation in infertile women.^47-62 In addition, AIs improved follicle development in poor responders, a finding that may be important for breast cancer survivors treated with adjunctive chemotherapy, who may have diminished ovarian reserve. We found estradiol levels to be significantly lower with the use of AIs compared to ovarian stimulation using other agents, especially CC, tamoxifen, or gonadotropins, despite the development of multiple ovarian follicles.^47-54 Both total estradiol levels as well as estradiol production per mature follicle were significantly lower with AI treatment.^47,54 In addition, it's possible to combine an AI with gonadotropin injections to obtain multiple follicle stimulation and still maintain estradiol levels in the physiologic range (consistent with mono-ovulatory estradiol concentrations).

We believe that the option of achieving multiple mature ovarian follicles while keeping estrogen levels within the physiologic range is an important potential advance in the fertility treatment of breast cancer survivors. The safety of these medications and the absence of any direct estrogenic activity make the use of aromatase inhibitors for ovulation induction in breast cancer survivors an exciting option.

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Dr. Mitwally is a Clinical Fellow, Reproductive Sciences Division, Department of Obstetrics and Gynecology, University of Toronto, and The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada, and Resident, Department of Gynecology and Obstetrics, University at Buffalo, School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, N.Y.; Dr. Casper is Professor, Reproductive Sciences Division, Department of Obstetrics and Gynecology, University of Toronto, and The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.

Key points

• Preliminary studies show that low-cost, oral third-generation aromatase inhibitors induce or augment ovulation induction in infertile women. They could circumvent many of the problems of clomiphene citrate and gonadotropins and make the treatment of infertility safer for breast cancer survivors.
• One hypothesis suggests that blocking estrogen production with AIs may release the hypothalamic/pituitary axis from estrogenic negative feedback, thereby increasing gonadotropin secretion and stimulating ovarian follicles.
• Overall pregnancy rates using AIs were significantly higher with letrozole-only and letrozole plus FSH when compared to clomiphene-only and compared to no stimulation cycles.
• The fact that AIs can improve follicle development in poor responders may be good news for breast cancer survivors treated with adjunctive chemotherapy, who may have diminished ovarian reserve.
• Many oncologists consider ovarian stimulation contraindicated for breast cancer survivors, mainly because it elevates estrogen levels. But now it's possible to combine an AI with gonadotropin injections to obtain multiple follicle stimulation and still maintain lower estradiol levels.

 

Robert Casper. Using aromatase inhibitors to induce ovulation in breast Ca survivors. Contemporary Ob/Gyn Jan. 1, 2004;49:73-83.