A historical perspective of aromatase inhibitors for ovulation induction.

The concept of using aromatase inhibitors in place of clomiphene citrate (CC) for ovulation induction was introduced >10 years ago; a brief history of its development is presented. Its worldwide usage for ovulation induction, including as an adjunct for intrauterine insemination and in vitro fertilization has occurred despite the absence of definitive data of superiority to CC. The results of two ongoing potentially definitive multicenter trials of efficacy and safety of letrozole compared with CC are eagerly awaited.

Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome.

Clomiphene citrate (CC) is the most commonly used oral agent for the induction of ovulation. It is a nonsteroidal selective estrogen receptor modulator that has predominant antiestrogenic action resulting in long-lasting estrogen receptor depletion. Side effects include antiestrogenic effects systemically and on the endometrium and cervical mucous. Letrozole is a potent, nonsteroidal, aromatase inhibitor, originally used for postmenopausal breast cancer therapy, at present its only registered indication. We hypothesized that letrozole could mimic the action of CC without depletion of estrogen receptors. As there is no estrogen receptor antagonism, antiestrogenic effects such as poor cervical mucus and thin endometrium are not expected with aromatase inhibitor treatment. In addition, because estrogen receptors in the brain are not depleted, normal negative feedback occurs with letrozole and generally results in monoovulation. We and others have demonstrated the success of aromatase inhibition in inducing ovulation in women with polycystic ovarian syndrome. Letrozole may be very effective for ovulation induction and pregnancy in cases of CC resistance. When used together with follicle-stimulating hormone (FSH) injections, letrozole resulted in a significant reduction in the FSH dose needed for controlled ovarian hyperstimulation. Aromatase inhibitors likely increase ovarian sensitivity to FSH, and may be useful in poor responders and in women undergoing ovarian stimulation for in vitro fertilization. The safety of letrozole in pregnancy outcome studies has been demonstrated by examination of spontaneous pregnancy loss, multiple pregnancy rates, and congenital anomalies compared with a control group of infertility patients treated with CC. In addition, new data suggest that CC may result in cardiac anomalies and other birth defects and in low birth weight babies. We believe aromatase inhibitors are acceptable alternatives to CC as first line oral agents for ovulation induction or controlled ovarian stimulation.

Endometrial thickness is related to miscarriage rate, but not to the estradiol concentration, in cycles down-regulated with gonadotropin-releasing hormone antagonist.

In this retrospective cohort study of 102 ovarian stimulation cycles for IVF/intracytoplasmic sperm injection using GnRH antagonist and gonadotropins, we sought to assess the effect of high E(2) levels on endometrial stripe thickness and its association with pregnancy outcomes and serum E(2) levels. We found no significant correlation between serum E(2) levels (both peak and area under the curve E(2) concentration) and the endometrial thickness. However, there was a statistically significant inverse relationship with early pregnancy loss (31%) if the endometrial thickness was <9.8 mm (sensitivity 71%; specificity 76%).

Fertility preservation and minimizing reproductive damage in cancer survivors.

Recent advances in oncology have helped in the survival and cure of increasing numbers of childhood cancer patients and those during their reproductive age period. This has increased the need to improve existing technology, and prompted the search for new technologies, to minimize the gonadotoxic effects of cancer treatment and preserve human fertility. Conservative surgical approaches for cancer treatment have been widely accepted following progress in early detection of cancer and accumulating long-term outcome safety data. Gonadal suppression to increase resistance to cancer treatment by gonadotropin analogues and sex hormones has been suggested. However, while this is unlikely to be effective in males, there is no general consensus on its success in the female. Fertility preservation options for both male and female patients include cryopreservation of embryos, gametes and gonads. While embryo cryopreservation is a well-established and successful technique, there are several obvious limitations. Gamete cryopreservation is very successful in males (sperm freezing) while still experimental in females (oocyte freezing), with growing evidence suggesting its potential success. Gonadal cryopreservation is still in its early stages of experimental development, both in males (testicular tissue cryopreservation and in vitro spermatogenesis) and female (ovarian tissue cryopreservation and in vitro follicular maturation).

Effect of cancer and cancer treatment on human reproduction.

Cancer affecting children and individuals of reproductive age is associated with dilemmas concerning the ability to have a child and whether this child will be healthy. This is particularly true in light of the recent advances in the early detection of cancer and its effective treatment, which has improved survival rates. Both the cancer itself and its treatment have tremendous adverse effects on human reproduction and may result in the complete termination of reproductive ability both in men and women. Even in situations when conception is successfully achieved following cancer diagnosis and treatment, there are concerns regarding the potential increased risk of adverse obstetric and perinatal outcomes. This is especially true when pregnancy occurs shortly after cancer treatment. Moreover, there is a potential risk of chromosomal abnormalities and malformations in the offspring due to possible genetic defects in the germ cells induced by chemotherapy and radiotherapy. In addition, there is (at least theoretically) an increased risk of cancer developing in the offspring, particularly with hereditary cancer syndromes. A multidisciplinary team aware of the possible consequences of cancer treatment on reproduction is very much needed to provide optimal care for these patients after proper counseling regarding the potential adverse effects of cancer treatment on reproduction.

Serum human chorionic gonadotropin level after ovulation triggering is influenced by the patient's body mass index and the number of larger follicles.

OBJECTIVE: To identify determinants of the serum concentration of hCG levels after triggering of ovulation with exogenous hCG during controlled ovarian stimulation cycles for in vitro fertilization with or without intracytoplasmic sperm injection. DESIGN: Retrospective cohort study. SETTING: University Medical Center. PATIENT(S): One hundred-fifteen women who underwent conventional in vitro fertilization/intracytoplasmic sperm injection cycles from March 2003 to March 2005. INTERVENTION(S): All patients underwent ovarian hyperstimulation with gonadotropins and GnRH-antagonist for pituitary downregulation. Patients were started on oral contraceptives 1 month before the stimulation. Gonadotropins were administered from stimulation day 1 until the day of the hCG trigger, and GnRH-antagonist was added from the day when at least one follicle reached 14 mm in diameter and continued until hCG administration. The hCG was administered in 5,000-IU, 10,000-IU, or 15,000-IU doses on the day of ovulation triggering. MAIN OUTCOME MEASURE(S): We performed a stepwise multiple regression analysis to predict which variable would influence the serum concentration of hCG when measured the day after the administration of exogenous hCG. RESULT(S): Body mass index (kg/m2) and number of follicles >14 mm were the only determinants of the hCG concentration (cumulative R2 = 0.30; P<.001). Patient age, estradiol peak, number of oocytes retrieved, length of stimulation, and length of GnRH-antagonist administration in days were not associated with serum hCG levels. CONCLUSION(S): Knowing that the number of larger follicles and the patient's BMI are the major determinants of the hormone's clearance in the body can help in the hCG dose titration during ovarian stimulation.

Potential of aromatase inhibitors for ovulation and superovulation induction in infertile women.

For almost half a century, the first-line treatment for ovulation induction in cases of anovulation, unexplained infertility, or mild male factor has been clomifene (clomiphene citrate). Clomifene is an effective and safely used oral agent, but is known to have relatively common antiestrogenic endometrial and cervical mucous adverse effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancies with clomifene compared with natural cycles. These drawbacks are mainly a result of the extended antiestrogenic effect of clomifene as a result of its accumulation in the body (clomifene isomers have a half-life of several days up to few weeks). Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of clomifene. Over the last few years several published studies, both controlled and noncontrolled, compared clomifene and treatment with aromatase inhibitors (AIs), either alone or in combination with gonadotropins, for ovulation induction or augmentation. These studies found AIs as effective as clomifene in inducing ovulation, with the major advantage of absence of any antiestrogenic adverse effects. Several other major advantages of AIs include the lower serum estrogen production per developing follicle resulting in more physiological estrogen levels around the time of ovulation and good pregnancy rates with a lower incidence of multiple pregnancy than with clomifene. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of gonadotropins required for optimal follicle recruitment and improve the response to gonadotropin stimulation in poor responders. Such preliminary evidence suggests that AIs may replace clomifene in the future because of similar efficacy with a reduced adverse-effect profile. However, we believe that definitive studies in the form of randomised controlled trials comparing clomifene with AIs are needed.

Estradiol production during controlled ovarian hyperstimulation correlates with treatment outcome in women undergoing in vitro fertilization-embryo transfer.

OBJECTIVE: To study the value of E(2) production during controlled ovarian hyperstimulation (COH) in predicting IVF-ET outcome. DESIGN: Historical cohort. SETTING: Academic infertility center. PATIENT(S): A cohort of 270 patients who completed 324 consecutive IVF-ET treatment cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Area under the curve for E(2) levels (AUC-E(2)) from the first day of COH until the day of hCG administration was calculated and cycles grouped into low, average, and high AUC-E(2) groups. Clinical pregnancy rates per cycle were compared among the three groups, and correlations with AUC-E(2) values were calculated for all patients and after sub-grouping according to age, COH protocol and infertility diagnosis. RESULT(S): Cycles with low and high AUC-E(2) values had significantly lower pregnancy rates particularly in patients 35 years or older. There was a positive correlation between AUC-E(2) and pregnancy rates up to a certain AUC-E(2) level above which a negative correlation was found. The turning point between positive and negative correlations occurred at a significantly lower AUC-E(2) level in patients 35 years or older. CONCLUSIONS: Estradiol production during COH correlates with IVF-ET outcome. Women >35 years of age seem more vulnerable to high E(2) levels.

Review: aromatase inhibitors for ovulation induction.

CONTEXT: For the last 40 yr, the first line of treatment for anovulation in infertile women has been clomiphene citrate (CC). CC is a safe, effective oral agent but is known to have relatively common antiestrogenic endometrial and cervical mucous side effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancy with CC, compared with natural cycles. Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of CC. The objective of this review was to describe the different physiological mechanisms of action for CC and aromatase inhibitors (AIs) and compare studies of efficacy for both agents for ovulation induction. EVIDENCE ACQUISITION: We conducted a systematic review of all the published studies, both controlled and noncontrolled, comparing CC and AI treatment, either alone or in combination with gonadotropins, for ovulation induction or augmentation, identified through the Entrez-PubMed search engine. EVIDENCE SYNTHESIS: Because of the recent acceptance of the concept of using AIs for ovulation induction, few controlled studies were identified, and the rest of the studies were pilot or preliminary comparisons. Based on these studies, it appears that AIs are as effective as CC in inducing ovulation, are devoid of any antiestrogenic side effects, result in lower serum estrogen concentrations, and are associated with good pregnancy rates with a lower incidence of multiple pregnancy than CC. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of FSH required for optimal follicle recruitment and improve the response to FSH in poor responders. CONCLUSIONS: Preliminary evidence suggests that AIs may replace CC in the future because of similar efficacy with a reduced side effect profile. Although worldwide experience with AIs for ovulation induction is increasing, at present, definitive studies in the form of randomized controlled trials comparing CC with AIs are lacking.

The role of aromatase inhibitors in ameliorating deleterious effects of ovarian stimulation on outcome of infertility treatment.

Clinical utilization of ovulation stimulation to facilitate the ability of a couple to conceive has not only provided a valuable therapeutic approach, but has also yielded extensive information on the physiology of ovarian follicular recruitment, endometrial receptivity and early embryo competency. One of the consequences of the use of fertility enhancing agents for ovarian stimulation has been the creation of a hyperestrogenic state, which may influence each of these parameters. Use of aromatase inhibitors reduces hyperestrogenism inevitably attained during ovarian stimulation. In addition, the adjunct use of aromatase inhibitors during ovarian stimulation reduces amount of gonadotropins required for optimum stimulation. The unique approach of reducing hyperestrogenism, as well as lowering amount of gonadotropins without affecting the number of mature ovarian follicles is an exciting strategy that could result in improvement in the treatment outcome by ameliorating the deleterious effects of the ovarian stimulation on follicular development, endometrial receptivity, as well as oocyte and embryo quality.

Area under the curve for estradiol levels do not consistently reflect estradiol levels on the day of hCG administration in patients undergoing controlled ovarian hyperstimulation for IVF-ET.

PURPOSE: Most studies reported estradiol (E2) levels attained on day of hCG administration when investigating effect of E2 on IVF outcome. We studied whether a relationship exists between the area under the curve for E2 levels (AUC-E2) and E2 levels on hCG day during IVF-ET. METHODS: Retrospectively, we analyzed data for 313 patients who completed one IVF-ET cycle each. Patients were sorted according to AUC-E2 levels. Then we compared between each patient's own AUC-E2 and the corresponding E2 level on hCG day for the same patient. RESULTS: Although overall AUC-E2 correlated positively with E2 levels on hCG day, there was no consistent correlation between individual patients. CONCLUSIONS: AUC-E2 reflects more accurately the amount of E2 produced by the follicles during controlled ovarian hyperstimulation. The absence of a uniform correlation between AUC-E2 and E2 on hCG day may result in different conclusions when studying outcomes of IVF treatment.

Single-dose administration of an aromatase inhibitor for ovarian stimulation.

Recently, the success of a 5-day administration of an aromatase inhibitor for ovarian stimulation has been shown. In this report, a convenient simple regimen of administering an aromatase inhibitor as a single dose has been found to have comparable success to a 5-day regimen for ovarian stimulation.

Aromatase inhibition reduces the dose of gonadotropin required for controlled ovarian hyperstimulation.

OBJECTIVE: To compare the use of the aromatase inhibitor, letrozole, in conjunction with follicle-stimulating hormone (FSH) injection, and FSH alone for controlled ovarian hyperstimulation (COH) in patients with polycystic ovarian syndrome (PCOS) or ovulatory infertility. METHODS: This nonrandomized study included two study groups: 26 patients with PCOS and 63 with ovulatory infertility (unexplained infertility [41 patients], male factor infertility [17 patients], and endometriosis [5 patients]), who received letrozole in addition to FSH; and two control groups: 46 PCOS patients and 308 with ovulatory infertility (unexplained infertility [250 patients], male factor infertility [42 patients], and endometriosis [16 patients], who received FSH only. All patients had intrauterine insemination (IUI). Main outcome measures included dose of FSH used per cycle, number of preovulatory follicles greater than 16 mm in diameter, cancellation rate, and pregnancy rate. RESULTS: The FSH dose required for ovarian stimulation was significantly lower when letrozole was used in both study groups compared to the control groups without a significant difference in number of follicles greater than 16 mm. IUI cancellation rate was significantly lower with letrozole treatment in PCOS patients. In women with PCOS, clinical pregnancy rate per completed IUI cycle was 26.5% in the letrozole plus FSH group versus 18.5% in the FSH-only group. In ovulatory infertility patients, the pregnancy rate was similar in both study and control groups (11%). CONCLUSION: We believe that inhibition of estrogen synthesis by aromatase inhibition will release the estrogenic negative feedback, resulting in an increase in endogenous FSH secretion. Moreover, by inhibiting conversion of androgens into estrogens, accumulating androgens may increase follicular sensitivity to FSH. Such a protocol has the potential to lower FSH treatment cost and may improve response for low responders who require high FSH doses during ovarian stimulation.

Endometriosis from thelarche to midteens: pathogenesis and prognosis, prevention and pedagogy.

John Huffman, a founder of the subspecialty of pediatric and adolescent gynecology in North America, first related the diagnosis of endometriosis to thelarche. Subsequently, endometriosis was diagnosed in early puberty between thelarche and menarche. Based on solid evidence, we suggest that the theory of embryonic mullerian rests be added to currently accepted theories of pathogenesis of endometriosis. This article argues for recognition of embryonic mullerian rests as the pathogenesis of some cases of endometriosis not explained by accepted theories. Along with Huffman, we propose that thelarche be recognized as a developmental benchmark, after which endometriosis is included in the differential diagnosis of chronic pelvic pain. Thus, in an effort to refocus research and patient care to early adolescence, this review is limited to endometriosis occurring in young women from thelarche to their sixteenth birthday. Relating endometriosis to thelarche has fundamental implications for pathogenesis, early diagnosis, prognosis, treatment, education, and long-term care of adolescents.

Aromatase inhibitors for the treatment of infertility.

Ovarian stimulation during infertility treatment is used either alone or in conjunction with intrauterine insemination and assisted reproductive technologies. At the present time, the two main medications used for ovarian stimulation include an oral antioestrogen, clomiphene citrate and injectable gonadotrophins. In spite of the high ovulation rate, the use of clomiphene citrate is associated with adverse side effects and low pregnancy rates. In clomiphene citrate failures, gonadotrophin injections are generally the next treatment option but, especially in polycystic ovarian syndrome, are associated with increased risk of severe ovarian hyperstimulation syndrome and high multiple pregnancies. Therefore, an effective oral treatment that could be used without risk of ovarian hyperstimulation syndrome and with minimal monitoring is preferred. It was hypothesised that aromatase inhibitors can be administered early in the follicular phase to induce ovulation by releasing the hypothalamus and/or pituitary from oestrogen negative feedback. The success of aromatase inhibitors in induction and augmentation of ovulation has been reported. In addition, increased intraovarian androgen levels may synergise with central effects of decreased oestrogen to enhance ovarian response to gonadotrophin stimulation. This increased sensitivity to follicle-stimulating hormone may be especially useful in poor responders. The potential future applications for aromatase inhibitors in infertility management are also discussed.

Effect of in vivo GnRH agonist and GnRH antagonist on hCG and insulin-stimulated progesterone production by human granulosa-lutein cells in vitro.

PURPOSE: To investigate hCG and insulin-stimulated progesterone (P) production by human granulosa-lutein cells (hGLC) in vitro. METHODS: hGLCs were isolated from patients undergoing IVF-ET cycles in which GnRH agonist or GnRH antagonist was used to prevent a midcycle gonadotropin surge. The cells were cultured for 3 days, and then treated with hCG 0.5, 1, and 10 IU/I, and insulin 0.01, 0.1, and 1 microM in serum free conditions. In vitro P production was measured by enzyme immunoassay. RESULTS: hCG stimulated P production by hGLCs from cycles in which GnRH antagonist was used, but a blunted response was seen in GnRH-agonist treated cycles. Insulin-stimulated P production was similar in cells from cycles in which GnRH-agonist or GnRH-antagonist treatment was used. CONCLUSIONS: Because insulin and hCG may share common pathways beyond the level of receptor activation, we hypothesize that GnRH agonist, but not GnRH antagonist, may affect the expression and/or activation of LH receptors in the hGLCs.