Karl R. Hansen

Correlation of ovarian reserve tests with histologically determined primordial follicle number

OBJECTIVE To investigate the relationship between clinical markers of ovarian reserve and the true ovarian reserve as determined by the ovarian primordial follicle number. DESIGN Prospective investigation. SETTING Academic medical center. PATIENT(S) Forty-two healthy women (aged 26-52 years) undergoing oophorectomy for benign gynecologic indications. INTERVENTION(S) Transvaginal ultrasound examination for the determination of the ovarian antral follicle count (AFC) and serum measurements of clinical markers of ovarian reserve. All measurements were obtained within 2 weeks of surgery, irrespective of cycle day. Ovarian primordial follicle count was then determined using a validated fractionator/optical disector method. MAIN OUTCOME MEASURE(S) Univariate and partial correlations between ovarian reserve markers and ovarian primordial follicle count. RESULT(S) There were significant correlations between the ovarian primordial follicle count and AFC (r=0.78), anti-Müllerian hormone (AMH; r=0.72), FSH (r=-0.32), inhibin B (r=0.40), and chronological age (r=-0.80). After adjusting for age, significant correlations were identified between the ovarian primordial follicle count and AFC (r=0.53) and AMH (r=0.48). CONCLUSION(S) The ovarian AFC and serum levels of AMH correlate with the ovarian primordial follicle number even after adjustment for chronological age.

A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause

BACKGROUND The primary determinant of reproductive age in women is the number of ovarian non-growing (primordial, intermediate and primary) follicles (NGFs). To better characterize the decline in NGF number associated with aging, we have employed modern stereology techniques to determine NGF number in women from birth to menopause. METHODS Normal human ovaries were collected from 122 women (aged 0-51 years) undergoing elective oophorectomy, organ donation or autopsy. After gross pathologic examination, systematic random sampling was utilized to obtain tissue for analysis by the fractionator/optical disector method. Models to describe the resulting decay curve were constructed and evaluated. RESULTS NGF decay was best described by a simple power function: log (y) = ax(b) + c, where a, b and c are constants and y = NGF count at age x (R(2) = 0.84, Sums of Squares Error = 28.18 on 119 degrees of freedom). This model implies that follicles decay faster with increasing age. CONCLUSIONS Unlike previous models of ovarian follicle depletion, our model predicts no sudden change in decay rate, but rather a constantly increasing rate. The model not only agrees well with observed ages of menopause in women, but also is more biologically plausible than previous models. Although the model represents a significant improvement compared with earlier attempts, a considerable percentage of the variation in NGF number between women cannot be explained by age alone.

Letrozole, gonadotropin, or clomiphene for unexplained infertility

BACKGROUND The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates. METHODS We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies. RESULTS After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications. CONCLUSIONS In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.).

Ovarian primordial and nongrowing follicle counts according to the Stages of Reproductive Aging Workshop (STRAW) staging system.

ObjectiveThe aim of this study was to characterize the ovarian primordial and nongrowing follicle number according to the Stages of Reproductive Aging Workshop (STRAW) staging system as defined by menstrual cycle characteristics. MethodsNormal ovaries were collected from 63 women (age 26-52 y) undergoing oophorectomy for benign indications. Before surgical operation, each participant completed a detailed questionnaire collecting information regarding menstrual cycle characteristics and was classified by bleeding patterns into STRAW stages −4, −3, −2, and −1. A single ovary was selected for the determination of ovarian primordial and total nongrowing follicle number using a validated fractionator/optical disector method. A subset of the participants (n = 43) underwent transvaginal ultrasound examination for the determination of the ovarian antral follicle count and serum measurements of follicle-stimulating hormone, estradiol, antimüllerian hormone, and inhibin B. All measurements were obtained within 2 weeks of surgical operation, irrespective of cycle day. ResultsSignificant differences were identified in ovarian primordial (P < 0.0001) and nongrowing follicle (P < 0.0001) counts across the STRAW stages. In post hoc testing, the differences in primordial follicle counts were significant between each of the STRAW stages. Significant differences were also identified in serum levels of antimüllerian hormone, follicle-stimulating hormone, and ovarian antral follicle count across the STRAW stages. ConclusionsProgression through the STRAW stages as defined by menstrual cycle characteristics is associated with progressive and significant decreases in the ovarian primordial follicle number.

Assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial: baseline characteristics

OBJECTIVE To identify baseline characteristics of women with unexplained infertility to determine whether treatment with an aromatase inhibitor will result in a lower rate of multiple gestations than current standard ovulation induction medications. DESIGN Randomized, prospective clinical trial. SETTING Multicenter university-based clinical practices. PATIENT(S) A total of 900 couples with unexplained infertility. INTERVENTION(S) Collection of baseline demographics, blood samples, and ultrasonographic assessments. MAIN OUTCOME MEASURE(S) Demographic, laboratory, imaging, and survey characteristics. RESULT(S) Demographic characteristics of women receiving clomiphene citrate (CC), letrozole, or gonadotropins for ovarian stimulation were very consistent. Their mean age was 32.2 ± 4.4 years and infertility duration was 34.7 ± 25.7 months, with 59% primary infertility. More than one-third of the women were current or past smokers. The mean body mass index (BMI) was 27 and mean antimüllerian hormone level was 2.6; only 11 women (1.3%) had antral follicle counts of <5. Similar observations were identified for hormonal profiles, ultrasound characterization of the ovaries, semen parameters, and quality of life assessments in both male and female partners. CONCLUSION(S) The cause of infertility in the couples recruited to this treatment trial is elusive, as the women were regularly ovulating and had evidence of good ovarian reserve both by basal FSH, antimüllerian hormone levels, and antral follicle counts; the male partners had normal semen parameters. The three treatment groups have common baseline characteristics, thereby providing comparable patient populations for testing the hypothesis that use of letrozole for ovarian stimulation can reduce the rates of multiples from that observed with gonadotropin and CC treatment. CLINICAL TRIAL REGISTRATION NUMBER NCT 01044862.

Chlamydia trachomatis immunoglobulin G3 seropositivity is a predictor of reproductive outcomes in infertile women with patent fallopian tubes

OBJECTIVE To determine if Chlamydia trachomatis (C. trachomatis) seropositivity, as detected by the C. trachomatis elementary body (EB)-based enzyme-linked immunosorbent assay [EB ELISA] predicts pregnancy and pregnancy outcome among infertile women with documented tubal patency. DESIGN Cohort study. SETTING Outpatient clinics. PATIENT(S) In all, 1,250 infertile women with documented tubal patency enrolled in 1 of 2 randomized controlled trials: Pregnancy in Polycystic Ovary Syndrome II; and the Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. INTERVENTION(S) Sera were analyzed for anti-C. trachomatis immunoglobulin G (IgG)1 and IgG3 antibodies, using a research C. trachomatis EB ELISA. The optical density (OD)405 readings of ≥ 0.35 and ≥ 0.1 were considered positive for IgG1 and IgG3, respectively. MAIN OUTCOME MEASURE(S) Primary outcomes included pregnancy, live birth, and ectopic pregnancy. Log-linear regression was used to determine the relative risk after adjusting for age, race, treatment medication, smoking status, and current alcohol use. RESULT(S) A total of 243 (19%) women were seropositive for anti-C. trachomatis IgG3. They tended to be nonwhite and smokers. Anti-C. trachomatis IgG3 seropositive women were significantly less likely to conceive (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.52-0.83) or to have a live birth (RR 0.59, 95% CI 0.43-0.80); these associations were weakened after adjusting for number of hysterosalpingography-documented patent tubes (RR 0.73, 95% CI 0.56-0.97) and (RR 0.73, 95% CI 0.50-1.04), respectively. Anti-C. trachomatis IgG3 seropositive women who conceived had a ×2.7 risk (95% CI 1.40-5.34) of ectopic pregnancy. CONCLUSION(S) Even in the presence of tubal patency, anti-C. trachomatis IgG3 seropositivity is associated with a lower likelihood of pregnancy. Anti-C. trachomatis IgG3 seropositive women have as high as 3 times the risk of ectopic pregnancy. CLINICAL TRIAL REGISTRATION NUMBER PPCOSII: NCT00719186 and AMIGOS: NCT01044862.

Smoking and infertility: a committee opinion

Approximately 21% of women of reproductive age and 22% of men of reproductive age in the United States smoke cigarettes. Substantial harmful effects of cigarette smoke on fecundity and reproduction have become apparent but are not generally appreciated. This committee opinion reviews the potential deleterious effects of smoking on conception, ovarian follicular dynamics, sperm parameters, gamete mutations, early pregnancy, and assisted reproductive technology (ART) outcomes. It also reviews the current status of smoking cessation strategies. This document replaces the 2012 ASRM Practice Committee document of the same name (Fertil Steril 2012;98:1400-6).

The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion

The value of preimplantation genetic testing for aneuploidy (PGT-A) as a screening test for in vitro fertilization (IVF) patients has yet to be determined. Several studies demonstrate higher birth rates after aneuploidy testing and elective single-embryo transfer (eSET), suggesting the potential for this testing to decrease the risk of multiple gestations, though these studies have important limitations.

Predictors of pregnancy and live birth after insemination in couples with unexplained or male-factor infertility

OBJECTIVE To identify risk factors for pregnancy outcomes in couples treated with intracervical or intrauterine insemination, with or without superovulation for unexplained or male-factor infertility. DESIGN Secondary analysis of data from a randomized superovulation and intrauterine insemination trial. SETTING Academic medical centers. INTERVENTION(S) Treatment continued for four cycles unless pregnancy was achieved. PATIENT(S) Out of 932 couples randomized to four treatment groups, 664 couples who had completed the lifestyle questionnaires were assessed for occurrence of pregnancy and live birth. MAIN OUTCOME MEASURE(S) Pregnancy and live birth. RESULT(S) The pregnancy and live birth rates were significantly higher in couples in which the female partners reported that they had consumed coffee or tea in the past or drank alcoholic beverages in the past (past users) compared with those who had never consumed coffee, tea, or alcoholic beverages. Past users also had significantly higher pregnancy and live birth rates than those currently consuming coffee or tea or alcoholic beverages. Demographic, occupational exposure, and other lifestyle factors were not significant. CONCLUSION(S) Couples in which the female partners drank coffee, tea, or alcoholic beverages in the past had higher pregnancy and live birth rates compared with never or current users. When discontinuing these habits, they might have made other lifestyle changes to improve the pregnancy outcome.

Performing the embryo transfer: a guideline

A systematic review of the literature was conducted which examined each of the major steps of embryo transfer. Recommendations made for improving pregnancy rates are based on interventions demonstrated to be either beneficial or not beneficial.