Fady I. Sharara

Environmental toxicants and female reproduction.

OBJECTIVE To review current knowledge on the potential effects of environmental toxicants on female reproduction in laboratory animals, wildlife, and humans. DESIGN Published literature about the effects of endocrine disruptors, heavy metals, solvents, pesticides, plastics, industrial chemicals, and cigarette smoke on female reproduction. RESULT(S) Published data indicate that chemical exposures may cause alterations in reproductive behavior and contribute to subfecundity, infertility, pregnancy loss, growth retardation, intrauterine fetal demise, birth defect, and ovarian failure in laboratory animals and wildlife. Data on the association of chemical exposures and adverse reproductive outcomes in humans are equivocal and often controversial. Some studies indicate that chemical exposures are associated with infertility, spontaneous abortion, or reproductive cancer in women. In contrast, other studies indicate that there is no association between chemical exposures and adverse reproductive outcomes. The reasons for ambiguous findings in human studies are unknown but likely include the fact that many studies are limited by multiple confounders, inadequate methodology, inappropriate endpoints, and small sample size. The mechanism by which chemicals alter reproductive function in all species is complex and may involve hormonal and/or immune disruption, DNA adduct formation, altered cellular proliferation, or inappropriate cellular death. CONCLUSION(S) Studies are needed to clarify which toxicants affect human reproduction and by which mechanisms of action. Furthermore, methods should be developed to minimize exposure to known reproductive toxicants such as dioxins and cigarette smoke.

The detection of diminished ovarian reserve in infertile women

Women in their mid to late 30s and early 40s with infertility constitute the largest portion of the total infertility population. These women frequently undergo multiple testing, and most will require expensive and invasive therapies, including assisted reproductive technologies, with markedly reduced pregnancy rates in those older than 40. These women also have a higher incidence of pregnancy loss even after documentation of fetal cardiac activity by ultrasonography. Identifying those women who have a very low chance of pregnancy (and a high chance of pregnancy loss) with their own gametes presents a daily challenge to the practicing clinician, especially before embarking on expensive treatments. This article reviews the contemporary investigation of reproductive aging with basal and provocative tests. Women with markedly diminished ovarian reserve should be counseled on their low chances of conception with their own gametes, even with assisted reproductive technologies.

Environmental toxicants and female reproduction 4

OBJECTIVE To review current knowledge on the potential effects of environmental toxicants on female reproduction in laboratory animals, wildlife, and humans. DESIGN Published literature about the effects of endocrine disruptors, heavy metals, solvents, pesticides, plastics, industrial chemicals, and cigarette smoke on female reproduction. RESULT(S) Published data indicate that chemical exposures may cause alterations in reproductive behavior and contribute to subfecundity, infertility, pregnancy loss, growth retardation, intrauterine fetal demise, birth defect, and ovarian failure in laboratory animals and wildlife. Data on the association of chemical exposures and adverse reproductive outcomes in humans are equivocal and often controversial. Some studies indicate that chemical exposures are associated with infertility, spontaneous abortion, or reproductive cancer in women. In contrast, other studies indicate that there is no association between chemical exposures and adverse reproductive outcomes. The reasons for ambiguous findings in human studies are unknown but likely include the fact that many studies are limited by multiple confounders, inadequate methodology, inappropriate endpoints, and small sample size. The mechanism by which chemicals alter reproductive function in all species is complex and may involve hormonal and/or immune disruption, DNA adduct formation, altered cellular proliferation, or inappropriate cellular death. CONCLUSION(S) Studies are needed to clarify which toxicants affect human reproduction and by which mechanisms of action. Furthermore, methods should be developed to minimize exposure to known reproductive toxicants such as dioxins and cigarette smoke.

In-vitro fertilization outcome in women with hydrosalpinx

Recent studies have suggested that the presence of hydrosalpinx has a negative effect on in-vitro fertilization (IVF) outcome, with markedly diminished implantation and pregnancy rates, and increased early pregnancy loss. We evaluated the impact of hydrosalpinx on IVF outcome in a large population with tubal factor infertility: 63 patients with hydrosalpinx and 60 without hydrosalpinx (no hydrosalpinx) underwent 103 and 89 IVF cycles respectively. Hydrosalpinx was diagnosed by hysterosalpingography and/or laparoscopy prior to IVF. Patients were further subdivided into those with or without elevated quantitative serum Chlamydia trachomatis IgG antibody (Ab) titres. All couples with elevated serum Ab titres (l: 16 or more) were treated with doxycycline (100 mg bid.) 10 days prior to the first IVF cycle. In all, 88 women (71.5%) had elevated C. trachomatis Ab: 47 women (74.6%) with hydrosalpinx had elevated titres, compared to 41 (68.3%) in the no hydrosalpinx group. There were no significant differences in mean age, number of mature oocytes obtained, and number of embryos transferred between the two groups. There was a trend for a higher implantation rate and ongoing pregnancy rate in the no hydrosalpinx group compared to the hydrosalpinx group (12.6 versus 9.8%, and 33.7 versus 24.8% respectively); however, this did not reach statistical significance. The incidence of early pregnancy loss was similar in the two groups. Two ectopic pregnancies were noted in the hydrosalpinx group compared to none in the no hydrosalpinx group. As expected, the prevalence of elevated titres of C. trachomatis IgG Ab in patients with tubal factor infertility presenting for assisted reproductive treatment was high. In contrast to recently published reports, our study did not confirm a negative effect of hydrosalpinx on IVF outcome when antibiotic treatment was given prior to assisted reproductive treatment. Prospective multicentre studies evaluating the effect of hydrosalpinx and its treatment on IVF outcome are needed.

Differences in in vitro fertilization (IVF) outcome between white and black women in an inner-city, university-based IVF program

OBJECTIVE To compare IVF outcomes between white and black women in an inner-city, university-based IVF program. DESIGN Retrospective study. SETTING University-based IVF program. PATIENT(S) Ninety-five white women undergoing 121 cycles and 37 black women undergoing 47 cycles. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Implantation rate and pregnancy rate (PR). RESULT(S) Black women constituted 28. 0% of the population and underwent 28.0% of the total cycles. There were no statistically significant differences in age, basal FSH, number of ampules, duration of stimulation, endometrial thickness, P on the day of hCG, cancellation rate, number of oocytes, or embryos transferred. However, the duration of infertility, body mass index (BMI), incidence of tubal-factor infertility, and peak E(2) levels were significantly higher in black women. In addition, a larger proportion of black women required aggressive stimulation than white women (70.2% and 43.0%). Both implantation rates and clinical PRs were significantly lower in black women than in white women (9.8% and 19.2% compared with 23.4% and 42.2%, respectively). CONCLUSION(S) Black women have poorer IVF outcomes than white women. These differences can be partly explained by higher BMI, longer duration of infertility, higher incidence of tubal-factor infertility, and higher peak E(2).

High estradiol levels and high oocyte yield are not detrimental to in vitro fertilization outcome

OBJECTIVE To evaluate the impact of elevated peak E2 levels and a high number of retrieved oocytes on implantation in patients undergoing assisted reproductive techniques. DESIGN Retrospective study. SETTING University-based IVF program. PATIENT(S) One hundred six patients undergoing 106 IVF cycles. High responders were defined as those who had peak E2 levels of >3,000 pg/mL on the day of hCG administration (n = 38) or >15 retrieved oocytes (n = 48). Their IVF outcomes were compared with those of patients whose peak E2 levels were < or =3,000 pg/mL (n = 68) or who had < or =15 retrieved oocytes (n = 58). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Implantation and pregnancy rates. RESULT(S) There were no statistically significant differences in age, basal FSH level, basal E2 level, number of ampules of gonadotropins required, fertilization rate, number of ETs, implantation rate, or pregnancy rate between normal and high responders or between women who did and did not become pregnant. In addition, no differences were detected when outcome was analyzed according to the stimulation regimen used. CONCLUSION(S) Elevated peak E2 levels and high oocyte yield are not detrimental to IVF outcome. More studies are needed to characterize the threshold E2 levels above which implantation rates are reduced.

The effect of aging on ovarian volume measurements in infertile women

OBJECTIVE To test the hypothesis that aging is associated with a decrease in ovarian volume, and that the FSH level and volume are correlated inversely. METHODS One hundred nine women who had 73 in vitro fertilization cycles and 36 ovulation induction cycles were analyzed. Basal FSH and estradiol (E2) levels were measured on cycle day 3, and ovarian volume was measured and antral follicles were counted on the day of starting gonadotropin. RESULTS The mean age (+/- standard deviation) was 32.6+/-4.7 years. The mean FSH was 6.9+/-2.4 IU/L. The mean ovarian volume was 6.0+/-4.7 cm3. There were no significant differences between the median volumes of the left and right ovaries in individual subjects (4.6 and 4.8 cm3, respectively; interquartile range 3.0-7.3 and 3.1-7.9; P = .79). There was a significant positive correlation between age and FSH level (R = .372, P<.001), but not between age and ovarian volume (R = .039, P = .69). A significant relation was noted between FSH and the number of follicles (H = 20.8, P<.001), but not between FSH and volume (R = .102, P = .29). There was a significant decrease in the number of follicles and a higher cycle cancellation rate in women with volume smaller than 3 cm3 compared with those with volume greater than 3 cm3. CONCLUSION Women with small ovarian volumes, low number of antral follicles, and normal basal FSH and E2 levels may have diminished ovarian reserve.

Evaluation of basal estradiol levels in assisted reproductive technology cycles

OBJECTIVE To determine if basal E(2) screening increases the diagnostic accuracy of basal FSH screening and to determine whether basal E(2) levels correlate with outcome in ART cycles. DESIGN Retrospective. SETTING Tertiary care center. PATIENT(S) Two thousand six hundred thirty-four infertility patients. INTERVENTION(S) Cycle outcome was evaluated after grouping patients by basal E(2) levels beginning at <20 pg/mL and extending to >100 pg/mL at 10 pg/mL increments. MAIN OUTCOME MEASURE(S) Retrieved oocytes, pregnancy rate, and cancellation rate. RESULT(S) Cancellation rates were significantly increased in patients with basal E(2) levels of <20 pg/mL or >/=80 pg/mL. Basal E(2) levels neither predicted pregnancy outcome nor correlated with ovarian response in those patients not canceled. CONCLUSION(S) Patients with basal E(2) levels of <20 pg/mL or >/=80 pg/mL had an increased risk for cancellation. Basal E(2) was predictive of stimulation parameters in patients 40 years or older. For those patients who proceeded to retrieval, there were no differences in pregnancy or delivery rates relative to basal E(2) levels. This suggests that irrespective of basal E(2) levels patients who produce more than three maturing follicles in response to stimulation have adequate ovarian reserve as evidenced by their pregnancy rates.

Ovarian volume and antral follicle counts as indicators of menopausal status.

ObjectiveRecent studies suggest that ovarian volume and antral follicle numbers may be sensitive, specific, and early indicators of menopausal status. The accuracy of these markers, however, has not been compared directly to more traditional markers [age and follicle-stimulating hormone (FSH) levels]. Thus, the purpose of this study was to test whether ovarian volume and antral follicle counts are more sensitive and specific markers of menopausal status than age or FSH levels. DesignPremenopausal (n = 34) and postmenopausal (n = 25) women between 40 and 54 years old received a transvaginal ultrasound for determination of ovarian volume and antral follicle numbers, provided blood for measurement of FSH levels, and completed a questionnaire. FSH levels, age, ovarian volume, and antral follicle numbers were compared using t tests. Receiver operating characteristic curves were generated to evaluate the sensitivity and specificity of each marker. ResultsPostmenopausal women had significantly higher FSH levels (p ≤ 0.0001), smaller ovarian volumes (p ≤ 0.002), and fewer antral follicles (p ≤ 0.002) than premenopausal women. Ovarian volume and antral follicle numbers had similar sensitivity (27.3–100%) and specificity (3.4–92.9%) in indicating postmenopausal status as FSH levels and age. ConclusionThese data suggest that ovarian volume and antral follicle numbers may be useful indicators of menopausal status.

Endometrial Pattern on the Day of Oocyte Retrieval Is More Predictive of Implantation Success than the Pattern or Thickness on the Day of hCG Administration

Purpose:Multiple studies have confirmed a lower implantation (IR) and pregnancy rate (PR) in women who exhibit a homogeneous pattern (pattern II) of the endometrium compared to a triple-line pattern (pattern I) on the day of hCG administration. However, no data are available to evaluate if patients alter their endometrial thickness and pattern between the day of hCG administration (DhCG) and the day of oocyte retrieval (DRET) and whether these changes adversely affect endometrial receptivity.Methods:We prospectively evaluated 86 women (mean age, 32.9 ± 3.8 years; range, 24–40 years) undergoing 103 IVF/ET cycles.Results:Pattern II was noted in 7 cycles (6.8%) on DhCG, compared to 96 cycles with pattern I (93.2%). However, 20 cycles (19.4%) had pattern II on DRET. The ongoing IR was 13.0% (3/23) in the pattern II group compared to 20.8% (76/365) in the pattern I group on DhCG(P = NS). However, a significant decrease in the ongoing IR, to 9.9% (7/71), was noted in pattern II, compared to 23.3% (71/305) in pattern I, on DRET(P = 0.019). There was no difference in age, basal FSH, peak E2, P4on the day of hCG, number of oocytes, number of ET, or endometrial thickness between pregnant and nonpregnant patients, or between patients with pattern I and those with pattern II. A trend toward higher progesterone levels on DhCGwas noted in women with pattern II (P = 0.078).Conclusions:Endometrial pattern, rather than thickness, on the day of oocyte retrieval appears to be an important prognosticator of endometrial receptivity.