Midluteal serum progesterone levels and pregnancy following ovulation induction with human follicle-stimulating hormone: results of a combined-data analysis.

OBJECTIVE: This retrospective analysis of combined data (one Phase II and three Phase III clinical trials) of patients with oligo- or anovulatory infertility aimed to evaluate the association between pregnancy and midluteal serum progesterone (P4) level following ovulation induction and hence the indicative value of P4 for ovulation and pregnancy achievement. STUDY DESIGN: All patients (n = 913) were treated with human follicle-stimulating hormone. Cycles (n = 1,554) with one or two serum P4 levels in the luteal phase (days 5-12) following human chorionic gonadotropin administration and complete data on cycle outcome were included. RESULTS: Clinical pregnancy was achieved in 295/1,554 (19.0%) cycles; 87.5% of these led to live births (16.6%/cycle). Including and excluding multiple pregnancy data, 88% and 86% of all live births had P4 values >10 ng/mL, respectively. Overall clinical pregnancy rate plateaued at midluteal P4 levels >25 ng/mL but, when multiple pregnancies were excluded, plateaued at 20-25 ng/mL and then decreased. Mean midluteal P4 levels were twice as high in multiple versus singleton pregnancies. CONCLUSION: A midluteal P4 level >10 ng/mL may represent an appropriate threshold for indication of ovulation resulting in live birth. Multiple pregnancies were associated with higher mean midluteal P4 levels.

Biological versus chronological ovarian age: implications for assisted reproductive technology.

BACKGROUND: Women have been able to delay childbearing since effective contraception became available in the 1960s. However, fertility decreases with increasing maternal age. A slow but steady decrease in fertility is observed in women aged between 30 and 35 years, which is followed by an accelerated decline among women aged over 35 years. A combination of delayed childbearing and reduced fecundity with increasing age has resulted in an increased number and proportion of women of greater than or equal to 35 years of age seeking assisted reproductive technology (ART) treatment. METHODS: Literature searches supplemented with the authors' knowledge. RESULTS: Despite major advances in medical technology, there is currently no ART treatment strategy that can fully compensate for the natural decline in fertility with increasing female age. Although chronological age is the most important predictor of ovarian response to follicle-stimulating hormone, the rate of reproductive ageing and ovarian sensitivity to gonadotrophins varies considerably among individuals. Both environmental and genetic factors contribute to depletion of the ovarian oocyte pool and reduction in oocyte quality. Thus, biological and chronological ovarian age are not always equivalent. Furthermore, biological age is more important than chronological age in predicting the outcome of ART. As older patients present increasingly for ART treatment, it will become more important to critically assess prognosis, counsel appropriately and optimize treatment strategies. Several genetic markers and biomarkers (such as anti-Müllerian hormone and the antral follicle count) are emerging that can identify women with accelerated biological ovarian ageing. Potential strategies for improving ovarian response include the use of luteinizing hormone (LH) and growth hormone (GH). When endogenous LH levels are heavily suppressed by gonadotrophin-releasing hormone analogues, LH supplementation may help to optimize treatment outcomes for women with biologically older ovaries. Exogenous GH may improve oocyte development and counteract the age-related decline of oocyte quality. The effects of GH may be mediated by insulin-like growth factor-I, which works synergistically with follicle-stimulating hormone on granulosa and theca cells. CONCLUSION: Patients with biologically older ovaries may benefit from a tailored approach based on individual patient characteristics. Among the most promising adjuvant therapies for improving ART outcomes in women of advanced reproductive age are the administration of exogenous LH or GH.

A phase I study of the pharmacokinetics, pharmacodynamics, and safety of single- and multiple-dose anastrozole in healthy, premenopausal female volunteers.

OBJECTIVE: To evaluate the pharmacokinetic, pharmacodynamic, and safety profiles of the aromatase inhibitor anastrozole in healthy, premenopausal women. DESIGN: Phase I, single-center study. SETTING: Infertility clinic. PATIENT(S): Twenty-six women with regular ovulatory cycles: 20 received either a single dose of 5 mg, 10 mg, 15 mg, or 20 mg anastrozole, or remained untreated; 6 received five daily doses of 10 mg or 15 mg anastrozole. INTERVENTION(S): Anastrozole was administered on cycle day 2 for the single-dose groups and on days 2-6 for the multiple-dose groups. Ultrasound follicular development and endometrial biopsies were performed. Safety was determined from adverse event reports and laboratory parameters. MAIN OUTCOME MEASURE(S): Pharmacokinetics, pharmacodynamics, and safety. RESULT(S): The pharmacokinetics of anastrozole were linear, predictable, and consistent with previously published data in healthy volunteers. In the single-dose groups, E2 levels reached their nadir 3-6 hours after administration, decreasing by an average of 39% from baseline. Follicle-stimulating hormone levels rose by 13%, 52%, 49%, and 75% in the 5-mg, 10-mg, 15-mg, and 20-mg groups, respectively, at approximately 24 hours after dosing. Most subjects recruited just one mature follicle, with no apparent effect on endometrial maturation. No safety concerns were noted. CONCLUSION(S): Anastrozole was well tolerated and suppressed E2 levels, with a resultant increase in FSH.

Anastrozole versus clomiphene citrate: which is better for ovulation induction?

Although anastrozole may be used as an oral therapeutic agent in ovulation induction, it is not recommended as a replacement for clomiphene citrate. On the basis of two phase 2 studies, anastrozole should be viewed as a second-tier therapy after clomiphene citrate in anovulatory patients.

Anastrozole single-dose protocol in women with oligo- or anovulatory infertility: results of a randomized phase II dose-response study.

OBJECTIVE: To compare the effects of anastrozole and clomiphene citrate (CC) on follicular development and ovulation in infertile women with ovulatory dysfunction. DESIGN: Phase II, prospective, randomized, assessor-blind, multicenter, dose-finding, noninferiority study. SETTING: Outpatient. PATIENT(S): Infertile women with ovulatory dysfunction, aged 18-35 years, and body mass index <35 kg/m(2). INTERVENTION(S): Single-dose anastrozole at 5 mg (n = 39), 10 mg (n = 39), 20 mg (n = 39), or 30 mg (n = 38) or a 5-day course of CC at 50 mg/d (n = 39) as starting doses. MAIN OUTCOME MEASURE(S): The primary endpoint was the ovulation rate in the first treatment cycle (cycle 1). Ovulation was defined as a midluteal phase serum P level ≥ 10 ng/mL or clinical pregnancy. RESULT(S): In cycle 1 the ovulation rates for a single dose of anastrozole at 5, 10, 20, and 30 mg were 46.2%, 41.0%, 23.1%, and 28.9%, respectively, whereas that for CC at 50 mg/d was 61.5%. Among women with fewer than six menses per year, the cumulative ovulation rates over three cycles were comparable in the anastrozole 5 mg (52.4%) and CC 50 mg/d (42.3%) groups. CONCLUSION(S): In terms of ovulation rates in cycle 1, single-dose anastrozole at 5, 10, 20, and 30 mg was not as effective as CC at 50 mg/d for 5 days (noninferiority was not shown).

Anastrozole vs. clomiphene citrate in infertile women with ovulatory dysfunction: a phase II, randomized, dose-finding study.

OBJECTIVE: To determine an effective multiple-dose regimen of anastrozole compared with clomiphene citrate (CC) to induce follicular growth and ovulation in infertile women with ovulatory dysfunction. DESIGN: Phase II, prospective, randomized, double-blind, multicenter, dose-finding, noninferiority study. SETTING: Outpatient. PATIENT(S): Infertile women (n = 271) with ovulatory dysfunction, aged 18-40 years, with body mass index <37 kg/m(2). INTERVENTION(S): Five days of anastrozole at 1, 5, or 10 mg/d or CC at 50 mg/d. MAIN OUTCOME MEASURE(S): The primary endpoint was the ovulation rate (mid-luteal phase serum P level ≥ 10 ng/mL or clinical pregnancy) in the first treatment cycle (cycle 1). RESULT(S): In cycle 1 the ovulation rates for anastrozole at 1, 5, and 10 mg/d were 30.4% (n = 24), 36.8% (n = 28), and 35.9% (n = 14), respectively, compared with 64.9% (n = 50) for CC at 50 mg/d. In up to three cycles of treatment, cumulative ovulation rates did not differ between groups. No cases of ovarian hyperstimulation syndrome were reported, and both anastrozole and CC were well tolerated. CONCLUSION(S): In terms of ovulation rates, 5-day anastrozole at 1, 5, and 10 mg/d was less effective than CC at 50 mg/d for cycle 1 (noninferiority was not shown).