sign in sign up
<<
Home , Aromatase inhibitor

Mohamed F.M. Mitwally, MD inhibitors, a new Dr. Mitwally is Reproductive Endocrinologist and Specialist, Reproductive Medicine and Fertility option for inducing ovulation Center, Colorado Springs, Colo. He is also Clinical Assistant Professor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics This class of drugs may boost the pregnancy rate and Gynecology, at the University in selected populations of New Mexico in Albuquerque. Robert F. Casper, MD Dr. Casper is Professor in the Reproductive Sciences Division, Department of Obstetrics and CASE 1 Ovulation begins, (TABLES 1 and 2, page 58). The strategies Gynecology, at the University but pregnancy does not follow presented here are suitable for general of Toronto in Toronto, Ontario. ObGyns and do not require sophisticat- Dr. Mitwally holds patents licensed to Serono for use of aromatase U.Y. is a 32-year-old woman who has been ed technology such as rapid hormonal inhibitors for infertility treatment. trying to conceive for 3 years. Her infertility is assays or transvaginal US. Dr. Casper has a licensing agreement ® Dowden Health Media with Ares-Serono for use of aromatase caused by associated with poly- Because this application is so new, inhibitors in assisted reproduction. cystic syndrome (PCOS). All other vari- with limited data published so far, much The use of aromatase inhibitors for induction ables are within physiologicCopyright limits—she has of the information presented here is of ovulation represents an off-label indication For personal use only that requires further investigation and is patent tubes and an unremarkable uterus, and based on our personal experience rather discouraged by manufacturers of the drugs. her partner has a normal semen analysis. than level-1 evidence, which is sorely She has undergone six cycles of treat- needed. ment with clomiphene citrate, with ovulation Of course, induction of ovulation IN THIS ARTICLE documented each time by ultrasonography is appropriate only after other specifi c (US) and measurement of luteal-phase pro- causes of anovulation or ovulatory dys- ❙ Avoid aromatase gesterone levels. Her endometrial thickness function are excluded, such as thyroid inhibitors in these is 4 to 6 mm around the day of ovulation. disorders, hyperprolactinemia, severe in- situations Would an aromatase inhibitor increase sulin resistance, and ovarian failure. Page 58 her chances of conceiving? Concerns about teratogenicity of AIs appear to be largely unfounded (see ❙ Why aromatase This patient is an excellent candidate for page 70 ). inhibitors using an aromatase are superior to inhibitor (AI). clomiphene The primary reason? She is unlikely Ovulation is good, Page 60 to benefi t from an increased dosage of but pregnancy is better clomiphene citrate because the dosage In women undergoing induction of ovu- ❙ Five pearls for that triggers ovulation is believed to be lation, there are two levels of success: inducing ovulation most appropriate—an increase above ovulation and pregnancy. Page 73 that level is not expected to improve the Clearly, the presence of other, non- chance of pregnancy. Moreover, con- ovulatory infertility factors—e.g., male ception is less likely after more than six infertility and tubal-uterine problems— cycles of clomiphene citrate.1,2 can prevent successful ovulation induc- In this article, we describe the in- tion from translating into pregnancy. duction of ovulation using AIs—a rela- We have reported3–9 on the suc- tively new, and off-label, application cessful use of AIs to stimulate the ova-

www.obgmanagement.com January 2008 • OBG MANAGEMENT 57

For mass reproduction, content licensing and permissions contact Dowden Health Media. Aromatase inhibitors

TABLE 1 Latest generation of AIs is more benign Aromatase inhibitors work best in these applications Many AIs have been developed over the past 30 years. The most recent are APPLICATION EVIDENCE third-generation agents that were ap- Induction of ovulation, particularly • Strong evidence from several proved mainly to suppress in women with polycystic ovary clinical trials production in postmenopausal women syndrome: • Accumulating evidence of with . Clinical failure of • fi rst-line agent consistent trend toward higher • after failure of clomiphene citrate pregnancy rate, compared with earlier generations of AIs for their ap- See case 1 on page 57 clomiphene citrate proved indication was mainly due to and case 2 on page 68 • Evidence of successful ovarian signifi cant adverse effects, lack of sat- stimulation and conception after isfactory potency, or lack of specifi c- failure of clomiphene citrate ity in inhibiting the aromatase Ovarian stimulation (superovulation) Strong evidence from several in ovulatory women with unexplained clinical trials without inhibiting other of 20 or -related infertility steroidogenesis. See case 3 on page 68 Third-generation AIs that are com- Use in conjunction with controlled Accumulating evidence of several mercially available in North America, ovarian hyperstimulation by advantages when used with Europe, and other parts of the world with intrauterine gonadotropins: include: insemination and assisted • Reduces the dosage of reproduction gonadotropins required • two preparations: an- • Improves ovarian response to astrozole (Arimidex) and gonadotropins (Femara) • Theoretical benefi t of reducing • one steroidal agent: the risk of severe ovarian hyperstimulation syndrome (Aromasin). Letrozole and are revers- ible, competitive agents with consider- TABLE 2 ably greater potency (more than 1,000 Avoid AIs in these situations times greater) than the fi rst-generation AI . At a dosage of 1 to SITUATION JUSTIFICATION 5 mg/day, they reduce estrogen levels by When clomiphene citrate fails to First try insulin sensitizers and other 97% to more than 99%. induce ovulation in a woman with measures to improve insulin action AIs are completely absorbed after insulin resistance (weight loss, exercise, and dietary oral administration, with a mean termi- See case 2 on page 68 modifi cations) nal half-life of approximately 45 hours When other causes of infertility Pregnancy is unlikely (besides ovulatory dysfunction) (range: 30–60 hours). Exemestane has a are likely shorter circulating half-life of approxi- When the patient has hypothalamic/ Ovarian stimulation is dependent on mately 9 hours, but may have a longer hypopituitary anovulation or ovarian capacity to produce endogenous effect because it is irreversible.21 failure gonadotropins and presence of Mild gastrointestinal (GI) distur- responding ovarian follicles bances account for most of the adverse events, and rarely limit therapy. ry and achieve pregnancy—even in women who fail to conceive after sev- eral treatment trials with clomiphene How AIs work citrate.4 Although we continue to accrue data on Other authors have conducted fur- the use of AIs to induce ovulation, the ther investigations that have confi rmed underlying mechanism of action has not our fi ndings and have recommended been studied. However, we believe that use of these agents for other aspects of AIs work both centrally (at the level of the infertility treatment, such as assisted re- and pituitary) and periph- production.10–19 erally (at the level of the ).22–28

CONTINUED

58 OBG MANAGEMENT • January 2008 Aromatase inhibitors

FIGURE

Aromatase inhibitors promote follicle development, then fade from the scene in time to prevent hyperovulation

AB Hypothalamus/ pituitary

E2 E2

FSH FSH AI

Administration of an aromatase inhibitor (AI) on cycle days 3 to 7 suppresses ovarian (E2) secretion, as shown in A, which reduces estrogen-negative feedback at the hypothalamus and pituitary. As a result, follicle-stimulating hormone (FSH) secretion increases, fostering growth of multiple ovarian follicles. The growing follicles, shown in B, cause estrogen levels to rise again, depressing FSH, and leading to monofollicular ovulation in most cases.

At the central level, AIs suppress that are deleterious to ovar- estrogen production by directly, specifi - ian follicles, studies in primates have cally, and potently inhibiting the aroma- demonstrated that androgens actually up- FAST TRACK tase enzyme (i.e., estrogen synthase, the regulate the expression of Aromatase inhibitors enzyme responsible for the synthesis of receptors, particularly follicle-stimulating estrogen). Because the aromatase en- hormone (FSH) receptors.30 This renders suppress estrogen zyme is expressed in various tissues the ovaries more sensitive to gonadotro- production in the and organs—most notably, the ovaries, pin stimulation—whether the gonadotro- ovaries, , and brain, and fat29—AIs suppress estrogen pins are endogenous or exogenous.22–28 production in all of those tissues, leading to a low serum estrogen level and low local estrogen level. Low estrogen levels Why AIs are superior are thought to release the hypothalamus to clomiphene and from their negative- Clomiphene citrate is a selective estro- feedback mechanism, thereby increasing gen receptor modulator (SERM) that production of endogenous gonadotro- is believed to induce ovulation through pins from the pituitary gland and stim- its antiestrogenic properties at the level ulating ovarian follicular development of the hypothalamus or pituitary gland, and ovulation (FIGURE). or both. Clomiphene down-regulates At the peripheral level, the aroma- estrogen receptors at this level, and the tase enzyme catalyzes the terminal step hypothalamus and pituitary gland react in the steroidogenesis cascade that con- as though the estrogen level is very low. verts androgens into estrogen. When This reverses the suppression of endog- Flynn that enzyme is inhibited, enzyme sub- enous gonadotropins by estrogen, and Maura

strate (androgens) is thought to accu- gonadotropin levels rise, stimulating ©

mulate. Contrary to the general belief ovarian follicular development. 2007

CONTINUED

60 OBG MANAGEMENT • January 2008 Aromatase inhibitors

The down-regulation of estrogen re- proved ovarian response to stimulation ceptors with clomiphene administration by gonadotropins5–7 using AIs in small, is not limited to the hypothalamus and nonrandomized, controlled trials, sev- pituitary gland, but also occurs periph- eral larger and better designed clini- erally at the endometrium and cervix, cal trials followed and supported our where it is not so desirable. When the fi ndings.10–19 cervix is affected, it becomes an unfavor- Clinical trials comparing AIs with able environment for sperm to penetrate, clomiphene citrate have consistently re- and when the endometrium is affected, ported a universal “trend” toward su- its hypoestrogenic status may reduce the periority of AIs in achieving pregnancy likelihood of embryo implantation—or despite comparable levels of success in may increase the risk of pregnancy loss if achieving ovulation.10,11,14,16–19 However, implantation occurs. these published clinical trials lacked ad- These peripheral antiestrogenic pro- equate sample size to defi nitively con- perties of clomiphene citrate may ac- fi rm the superiority of AIs in achieving count for the discrepancy between high clinical pregnancy. We believe AIs are ovulation and low pregnancy rates.22–28 superior because, in our experience, they Several strategies to overcome this prob- have helped women achieve pregnancy lem—e.g., adding estrogen, starting clo- even after failure of several cycles of clo- miphene citrate earlier in the menstrual miphene treatment.4,15 period, or using another SERM, such as —have been largely unsuccess- ful. With clomiphene citrate, depletion of Should an AI follow estrogen receptors has long-term effects a trial of clomiphene? because of the drug’s relatively long half- U.Y., the patient described at the opening life (several days).31 of this article, has two main options now In contrast, AIs do not appear to af- that she has completed six cycles of clo- fect the expression of estrogen receptors miphene citrate without conceiving. The in different body tissues, such as the en- usual strategy would be a shift to more FAST TRACK dometrium and cervix. AIs have a shorter sophisticated treatment using gonadotro- Aromatase half-life (8 hours to 2 days), and non- pin injection. However, exogenous go- steroidal third-generation agents have a nadotropins have several disadvantages: inhibitors do not reversible inhibitory effect on the aroma- • the drugs must be injected appear to affect tase enzyme. Moreover, the rise in endog- (orally inactive) expression of enous gonadotropins stimulates the pro- • they are more expensive than estrogen receptors duction of more aromatase enzyme. This clomiphene citrate and AIs in the endometrium newly formed aromatase enzyme, and the • they require close monitoring by an return of a normal aromatase level after infertility specialist with expensive and cervix a short half-life of AI, leads the matur- and sophisticated technology ing ovarian follicles to secrete estrogen, • they carry a risk of severe ovarian hy- which reaches a physiologic level soon perstimulation, which is unlikely with after the last administration of AI. The clomiphene citrate and unreported rising estrogen level allows development with AIs of a more hospitable uterine environment • multiple pregnancy is likely, particu- (endometrium and cervical mucus).22–28 larly in conjunction with intrauterine insemination • the risk of ovarian hyperstimulation Early evidence with gonadotropin injection is much confi rms effi cacy of AIs higher in women with PCOS, such as After our pioneering reports of suc- U.Y., as is the likelihood of multiple cessful ovulation induction3–9 and im- pregnancy.

CONTINUED www.obgmanagement.com January 2008 • OBG MANAGEMENT 63 Aromatase inhibitors

The reason U.Y. has not conceived levels, most notably high FSH on day 3 after six cycles of clomiphene citrate is of the menstrual cycle. likely related to the drug’s antiestrogenic AIs are unlikely to induce ovula- effects on the endometrium, which ap- tion in either of these patients. For the peared to be very thin (4–6 mm) on US fi rst type of patient, exogenous gonado- imaging around the day of ovulation. If tropin injection would be appropriate, she fails to conceive with AIs, she will as would be a gonadotropin-releasing probably not become pregnant after a hormone (GnRH) pump. For a woman switch to gonadotropin injection unless with reduced ovarian reserve, an oocyte more advanced treatment is included, donor and IVF are the best treatment such as in vitro fertilization (IVF) and em- option. bryo transfer. Other causes of her infertil- Success with an AI is unlikely when ity—besides ovulatory dysfunction—may there is no appropriate indication for clo- explain the failure to conceive. miphene citrate. For example, a woman Comparable pregnancy rates have with severe insulin resistance who fails been observed for AIs and gonadotropin to ovulate in response to clomiphene ci- injection, although further study is need- trate is unlikely to ovulate in response ed—specifi cally, clinical trials comparing to an AI. In that case, an insulin sensi- gonadotropin and AIs in conjunction tizer—alone or in combination with clo- with timed intercourse or intrauterine in- miphene citrate or an AI—would be the semination, or both. appropriate option. Other measures to reduce insulin resistance, such as weight CASE 2 No response loss, exercise, and dietary modifi cation, to clomiphene citrate may also be helpful.

G.A., 28 years old, has been trying to conceive CASE 3 Ovulatory patient with for 3 years. She reports having irregular men- endometriosis fails to conceive strual periods indicative of anovulation, and on clomiphene FAST TRACK body temperature charts and progesterone Success with an levels support that diagnosis. She undergoes R.C., 34 years old, has been trying to conceive three cycles of clomiphene citrate at dosages for 2 years. Her basic infertility workup, which aromatase ranging from 50 to 150 mg/day for 5 days included a hysterosalpingogram and semen inhibitor is unlikely starting on day 3 of the menstrual cycle. De- analysis, did not reveal any abnormalities. when there is spite treatment, she fails to ovulate. She has regular menstrual cycles suggestive no appropriate Would an AI increase her chance of of ovulation. In addition, luteal-phase proges- indication for ovulating and conceiving? terone levels and biphasic body temperature charts both indicate regular ovulation. clomiphene citrate Failure to ovulate after treatment with After six cycles of clomiphene citrate, clomiphene citrate may have any of sev- her gynecologist performs diagnostic eral causes, including inappropriate pa- laparoscopy. Other than minimal, stage 1 tient selection and resistance to the drug. endometriosis, confi rmed by pathologic An example of inappropriate patient examination of peritoneal biopsies, there selection would be a woman with hypo- are no remarkable fi ndings. Methylene blue thalamic/hypopituitary anovulation; this tubal perfusion confi rms patent fallopian type of patient often has insuffi cient levels tubes during the operation. The gynecolo- of endogenous gonadotropins (luteiniz- gist fulgurates the minimal endometriotic ing hormone and FSH). Another example implants using carbon dioxide laser. Two would be a woman with reduced ovarian months after the procedure, the patient reserve; this type of patient is often unre- undergoes three more cycles of clomiphene sponsive to clomiphene citrate and may citrate, without success. have substantially elevated gonadotropin Would an AI help her conceive?

68 OBG MANAGEMENT • January 2008

668_r1_OBGM01088_r1_OBGM0108 68 12/19/07 6:45:26 PM Most of the data on successful treat- TABLE 3 ment with clomiphene citrate come from Basic infertility workup anovulatory women with PCOS in whom anovulation is the main cause of infertil- • Detailed medical history and physical examination ity. Evidence is weaker when the patient • Preconception counseling, including screening for genetic disorders is ovulatory and has unexplained or en- and counseling for high-risk pregnancy, if necessary dometriosis-associated infertility.32 • Initiation of prenatal vitamins and lifestyle modifi cations such as weight A recent nonrandomized, controlled loss, smoking cessation, and a reduction in alcohol and caffeine intake study that included women with a medi- • Basic testing that includes semen analysis; menstrual cycle day 3 FSH, , and thyroid-stimulating hormone serum levels; and imaging to cal history comparable to R.C.’s found check for tubal or uterine disorders, including one or more of the following: treatment with clomiphene citrate to sig- - hysterosalpingography to assess the tubes and uterine cavity nifi cantly reduce the chance of pregnancy, - pelvic ultrasonography to assess the uterine wall and ovaries and, compared with timed intercourse without occasionally, the tubes (if there is a suspicion of hydrosalpinx) clomiphene or other forms of ovarian - sonohysterography to evaluate abnormalities of the uterine cavity and, stimulation, following conservative lapa- in some cases, the tubes 33 roscopic surgery for their endometriosis. • Any further investigation indicated by the fi ndings We believe that clomiphene citrate is in- appropriate in women with endometrio- sis-related infertility—and may activate • semen analysis is within normal underlying endometriotic lesions. limits For R.C., treatment with an AI is a vi- • ovarian function is present—i.e., able option, particularly in light of recent the patient is expected to ovulate data showing that the aromatase enzyme in response to ovarian stimulation is expressed in endometriotic lesions.34 An • at least one tube is patent and AI could also enhance conception by fur- functional ther suppressing endometriosis through • uterus has no serious abnormalities. its effects on circulating estrogen levels If ovarian stimulation fails to trigger and local estrogen production. This is an ovulation or pregnancy, consider the op- unproven extrapolation that seems scien- tions listed in TABLE 4 (page 70). FAST TRACK tifi cally appropriate to us, but needs con- Because the fi rmation by randomized clinical trials. Minimal adverse effects aromatase enzyme CASE 4 Woman with unexplained— AIs are generally well tolerated. The most is expressed in and uninvestigated—infertility common adverse effects are hot fl ushes, endometriotic GI disturbances (nausea and vomiting), lesions, aromatase E.D., 31 years old, has been trying to conceive and leg cramps. In clinical trials involv- inhibitors may have for 1 year. Neither she nor her husband has un- ing postmenopausal women with breast dergone any study of their infertility problem. cancer who were taking an AI, very few the added benefi t Would empiric treatment with an AI be withdrew because of drug-related ad- of suppressing appropriate? verse effects.35 Those women took an endometriosis AI on a daily basis over several months. No treatment should begin until the pa- Fewer adverse effects would be expected tient and her partner have undergone among usually healthy younger women the basic workup (TABLE 3). If a specifi c administered a short course (a few days) cause of infertility is determined, the for ovarian stimulation. In addition, our patient should be treated accordingly. clinical experience has been that fewer If no explanation for the infertility can women experience side effects such as be found, or anovulation is the likely mild hot fl ushes and symptoms similar cause, empirical ovarian stimulation to premenstrual syndrome when tak- with timed intercourse or intrauterine ing an AI, compared with clomiphene insemination is reasonable, provided: citrate.3–9

CONTINUED

www.obgmanagement.com January 2008 • OBG MANAGEMENT 69

69_r1_OBGM0108 69 12/19/07 6:45:30 PM Aromatase inhibitors

TABLE 4

When ovarian stimulation fails, next step depends on several variables

LEVEL OF FAILURE CLOMIPHENE CITRATE AROMATASE INHIBITORS 1–No ovulation Is indication appropriate? Neither clomiphene citrate nor AIs are appropriate for hypothalamic/hypopituitary anovulation or ovarian failure Is severe insulin resistance present? If so, consider insulin sensitizers and encourage exercise, dietary changes, and weight loss Other options: Change to AI or retry Other options: Try adding an insulin clomiphene citrate in conjunction with sensitizer. If treatment fails after 3 to 6 an insulin sensitizer. If treatment fails additional cycles, consider an injectable after 3 to 6 additional cycles, consider gonadotropin an injectable gonadotropin 2–Ovulation Was another cause of infertility (besides ovulatory dysfunction) but no overlooked? Investigate further, if necessary pregnancy Options: Consider AIs before injectable gonadotropins, especially when there is evidence, with clomiphene citrate, of a persistent antiestrogenic effect, such as thin endometrium around the time of ovulation; endometriosis; or unexplained infertility. Move to gonadotropins if AIs fail

Are AIs teratogenic? 394 pregnancies achieved after treat- When any is given during ment with letrozole (133 pregnancies) pregnancy, there are concerns about its and other ovarian-stimulation agents, effects. Drugs used to induce ovulation including clomiphene citrate (113 preg- are no exception. In fact, clomiphene ci- nancies) and gonadotropins (110 preg- trate is classifi ed as pregnancy category nancies), with a control group of 38 X—a fact frequently overlooked by treat- pregnancies achieved without ovarian FAST TRACK ing physicians. As for AIs, recent studies stimulation.9 The study encompassed In a recent found no evidence of teratogenicity or three tertiary referral centers over 2 clastogenicity in animal embryos when years. Pregnancies conceived after treat- study, letrozole anastrozole was given. The picture is ment with an AI had rates of miscarriage was associated with murkier for letrozole. and ectopic pregnancy comparable to a signifi cantly lower When used for ovarian stimulation, all other groups. In addition, letrozole rate of multiple the short half-life of AIs and administra- was associated with a signifi cantly low- gestation than was tion in the early follicular phase (several er rate of multiple gestation than was days before ovulation and fertilization clomiphene citrate.9 clomiphene citrate occur) should ensure clearance of the The second study, presented in ab- drugs before implantation. Neverthe- stract form, compared the outcome of less, it is important to confi rm that the 150 births after treatment with letrozole patient is not pregnant before an AI is to a database of 36,050 normal deliver- given. We recommend a pregnancy test ies.36 Although the authors themselves before administering an AI for ovulation stated that there was no statistically induction. signifi cant difference in the overall inci- dence of congenital malformation, they Mixed bag of data reported a higher incidence of locomo- on pregnancy outcomes tor malformation and cardiac anomaly Three large studies recently reported in the infants conceived after treatment on pregnancy outcomes after infertility with letrozole.36 They did not address treatment with AIs.9,36,37 The fi rst was this discrepancy or explain how loco- a cohort study comparing outcomes of motor malformation was assessed.

CONTINUED

70 OBG MANAGEMENT • January 2008 Aromatase inhibitors

A closer look at the abstract reveals major methodological fl aws that weaken 5 pearls for inducing ovulation the data and conclusions presented: When using clomiphene citrate or an aromatase inhibitor (AI): The study was not well controlled. • • avoid a dosage that exceeds 100 to 150 mg/day for The treated patients (n = 130) were in- clomiphene citrate or 2.5 to 5 mg/day for AIs or a treatment fertile women, mainly suffering from period longer than 5 days each cycle PCOS and unexplained infertility, who • do not administer an AI beyond day 7 of the menstrual cycle had a mean age of 35.2 years. The con- trol group included a database of spon- • stop after three to six cycles of treatment taneously conceiving women who were • do not increase the dosage once ovulation occurs signifi cantly younger (mean age: 30.5 • discontinue treatment when serious adverse effects years). The control group also included are present, such as visual side effects. deliveries in a low-risk hospital that refers out high-risk pregnancies to sec- ondary and tertiary hospitals. These are It is also interesting that the results of important distinctions because women this abstract have not been published in of advanced maternal age have an in- a peer-reviewed journal more than a year creased incidence of medical illnesses, after its presentation. making their pregnancies higher in risk. The third study, which is more re- • The incidence of multiple gestation cent, compared the incidence of congeni- was signifi cantly higher among women tal malformation in 911 newborns con- treated for infertility than among wom- ceived after treatment with letrozole (n en in the control group. It is well known = 514) or clomiphene citrate (n = 397).37 that multiple gestations are at increased It found no statistically signifi cant dif- risk of fetal malformation compared ference between the groups. Congenital with singleton pregnancies. malformation was diagnosed in 2.4% • The incidence of cardiac anomaly and 4.8% of the letrozole- and clomi- among women treated with letrozole phene-treated groups, respectively, and did not differ signifi cantly from the major malformation occurred in 1.2% FAST TRACK known incidence of cardiac malforma- and 3% of the letrozole- and clomi- A large study found tion in the general population, but the phene-treated groups, respectively. These authors concluded that the rate of cardi- differences were not statistically signifi - a similar incidence ac malformation was signifi cantly high- cant, but there was a sevenfold increase of cardiac anomaly er in the letrozole group than among in overall cardiac anomalies in the clomi- among women controls. This is misleading because it phene-treated group, compared with the treated with was the control group that developed letrozole-treated group—and this differ- letrozole and the cardiac malformation at a signifi cantly ence was statistically signifi cant. These lower rate than in the general popula- fi ndings warrant further investigation general population tion. Such a low incidence of cardiac into the use of clomiphene citrate for in- anomaly in a low-risk hospital setting is duction of ovulation. ■ not surprising, because mothers would be transferred to a tertiary-care center References once an anomaly was detected. 1. Dickey RP, Taylor SN, Lu PY, Sartor BM, Rye PH, • Data on congenital malformation in Pyrzak R. Effect of diagnosis, age, sperm quality, and the control group were collected from number of preovulatory follicles on the outcome of delivery records available in the ma- multiple cycles of clomiphene citrate–intrauterine in- semination. Fertil Steril. 2002;78:1088–1095. ternity ward of the hospital. However, 2. Imani B, Eijkemans MJ, te Velde ER, Habbema JD, a signifi cant percentage of congenital Fauser BC. Predictors of chances to conceive in ovu- malformations, such as cardiac anom- latory patients during clomiphene citrate induction of aly, are not detected until after the neo- ovulation in normogonadotropic oligomenorrheic in- natal period.36 fertility. J Clin Endocrinol Metab. 1999;84:1617–1622.

CONTINUED www.obgmanagement.com January 2008 • OBG MANAGEMENT 73 Aromatase inhibitors

3. Mitwally MFM, Casper RF. Aromatase inhibition: 19. Bayar U, Basaran M, Kiran S, Coskun A, Gezer S. Use a novel method of ovulation induction in women of an aromatase inhibitor in patients with polycystic with polycystic ovarian syndrome. Reprod Technol. ovary syndrome: a prospective randomized trial. Fertil 2000;10:244–247. Steril. 2006;86:1447–1451. 4. Mitwally MFM, Casper RF. Use of an AI for induction 20. Buzdar A, Howell A. Advances in aromatase inhibi- of ovulation in patients with an inadequate response to tion: clinical effi cacy and tolerability in the treatment of clomiphene citrate. Fertil Steril. 2001;75:305–309. breast cancer. Clin Cancer Res. 2001;7:2620–2635. 5. Mitwally MFM, Casper RF. Aromatase inhibition im- 21. Winer EP, Hudis C, Burstein HJ, et al. American Society proves ovarian response to follicle-stimulating hormone of Clinical Oncology Technology Assessment on the use in poor responders. Fertil Steril. 2002;77:776–780. of aromatase inhibitors as adjuvant therapy for women 6. Mitwally MF, Casper RF. Aromatase inhibition reduces with hormone receptor–positive breast cancer: status gonadotropin dose required for controlled ovarian report 2002. J Clin Oncol. 2002;2015:3317–3327. stimulation in women with unexplained infertility. Hum 22. Mitwally MF, Casper RF. Potential of aromatase inhibi- Reprod. 2003;188:1588–1597. tors for ovulation and superovulation induction in in- 7. Mitwally MF, Casper RF. Aromatase inhibition reduces fertile women. Drugs. 2006;66:2149–2160. the dose of gonadotropin required for controlled 23. Mitwally MFM, Casper RF. Letrozole for ovulation in- ovarian hyperstimulation. J Soc Gynecol Investig. duction. Exp Rev Obstet Gynecol. 2006;1:15–27. 2004;11:406–415. 24. Casper RF, Mitwally MF. Review: aromatase inhibi- 8. Mitwally MFM, Casper RF. Single dose administration tors for ovulation induction. J Clin Endocrinol Metab. of the aromatase inhibitor, letrozole: a simple and con- 2006;91:760–771. venient effective method of ovulation induction. Fertil 25. Mitwally MF, Casper RF, Diamond MP. The role of aro- Steril. 2005;83:229–231. matase inhibitors in ameliorating deleterious effects of 9. Mitwally MFM, Casper RF. Pregnancy outcome after ovarian stimulation on outcome of infertility treatment. the use of an AI for induction of ovulation. Am J Obstet Reprod Biol Endocrinol. 2005;3:54. Gynecol. 2005;192:381–386. 26. Mitwally MF, Casper RF. Aromatase inhibitors in ovula- 10. Fatemi HM, Kolibianakis E, Tournaye H, et al. Clomi- tion induction. Semin Reprod Med. 2004;22:61–78. phene citrate versus letrozole for ovarian stimulation: a 27. Mitwally MF, Casper RF. Aromatase inhibitors for the pilot study. Reprod Biomed Online. 2003;75:543–546. treatment of infertility. Expert Opin Investig Drugs. 11. Al-Fozan H, Al-Khadouri M, Tan SL, Tulandi T. A ran- 2003;12:353–371. domized trial of letrozole versus clomiphene citrate 28. Mitwally MF, Casper RF. Aromatase inhibition for ovar- in women undergoing superovulation. Fertil Steril. ian stimulation: future avenues for infertility manage- 2004;82:1561–1563. ment. Curr Opin Obstet Gynecol. 2002;14:255–263. 12. Goswami SK, Das T, Chattopadhyay R, et al. A ran- 29. Cole PA, Robinson CH. Mechanism and inhibi- domized single-blind controlled trial of letrozole as tion of cytochrome P-450 aromatase. J Med Chem. a low-cost IVF protocol in women with poor ovar- 1990;33:2933–2944. ian response: a preliminary report. Hum Reprod. 30. Weil S, Vendola K, Zhou J, Bondy CA. and 2004;19:2031–2035. follicle-stimulating hormone interactions in primate 13. Garcia-Velasco JA, Moreno L, Pacheco A, et al. The ovarian follicle development. J Clin Endocrinol Metab. aromatase inhibitor letrozole increases the concentra- 1999;848:2951–2956. tion of intraovarian androgens and improves in vitro 31. Mikkelson TJ, Kroboth PD, Cameron WJ. Single dose fertilization outcome in low responder patients: a pilot pharmacokinetics of clomiphene citrate in normal vol- study. Fertil Steril. 2005;84:82–87. unteers. Fertil Steril. 1986;46:392–396. 14. Bayar U, Tanrierdi HA, Barut A, et al. Letrozole vs. 32. Hughes E, Collins J, Vandekerckhove P. Clomiphene clomiphene citrate in patients with ovulatory infertility. citrate for unexplained subfertility in women. Cochrane Fertil Steril. 2006;85:1045–1048. Database Syst Rev. 2000;(2):CD000057. 15. Elnashar A, Fouad H, Eldosoky M, et al. Letrozole 33. Mitwally MF, Albuarki H, Ashraf M, Diamond MP, induction of ovulation in women with clomiphene ci- Abuzeid M. Clomiphene reduces chance of pregnancy trate-resistant polycystic ovary syndrome may not de- in infertile women with endometriosis following lapa- pend on the period of infertility, the body mass index, roscopic surgery. J Soc Gynecol Investig. 2006;13(2) or the /follicle stimulating hormone (suppl): abstract 646. ratio. Fertil Steril. 2006;85:161–164. 34. Attar E, Bulun SE. Aromatase and other steroidogenic 16. Atay V, Cam C, Muhcu M, et al. Comparison of letro- genes in endometriosis: translational aspects. Hum zole and clomiphene citrate in women with polycystic Reprod Update. 2006;12:49–56. ovaries undergoing ovarian stimulation. J Int Med Res. 2006;34:73–76. 35. Goss PE. Risks versus benefi ts in the clinical appli- cation of aromatase inhibitors. Endocr Relat Cancer. 17. Sohrabvand F, Ansari S, Bagheri M. Effi cacy of com- 1999;6:325–332. bined metformin–letrozole in comparison with met- formin–clomiphene citrate in clomiphene-resistant 36. Biljan MM, Hemmings R, Brassard N. The outcome infertile women with polycystic ovarian disease. Hum of 150 babies following the treatment with letrozole or Reprod. 2006;21:1432–1435. letrozole and gonadotropins [abstract no. 1033]. Fertil Steril. 2005;84 (suppl): abstract 1033. 18. Sipe CS, Davis WA, Maifeld M, Van Voorhis BJ. A prospective randomized trial comparing anastrozole 37. Tulandi T, Martin J, Al-Fadhli R, et al. Congenital mal- and clomiphene citrate in an ovulation induction pro- formations among 911 newborns conceived after in- tocol using gonadotropins. Fertil Steril. 2006;86:1676– fertility treatment with letrozole or clomiphene citrate. 1681. Fertil Steril. 2006;85:1761–1765.

74 OBG MANAGEMENT • January 2008