Supraphysiological E2 Levels Research Articles

Estradiol production during controlled ovarian hyperstimulation correlates with the birth weight in pregnancies achieved after in vitro fertilization

To study correlation between E2 levels attained during COH and birth weight in pregnancies achieved after IVF-ET Retrospective analysis The study included 99 consecutive live births achieved in 61 singleton and 19 twin pregnancies after IV-ET. 9 singleton and 15 twin pregnancies ended in preterm labor (<37 wks). Gestational age was calculated from day of embryo transfer till day of delivery considering embryo transfer day as gestation day 17 (when day 3 embryos were transferred and day 19 when day 5 embryos were transferred). Birth weight was calculated as percentage from the birth weight expected according to gestational age (expected birth weight was calculated from a control population group similar to Western New York region that matched with the patients who underwent IVF-ET). E2 production during COH was calculated as area under the curve for E2levels (AUC-E2) from first day of COH until the day of hCG administration. The mean for birth weights (expressed as % from expected weight) was compared among singletons and twins after subdividing according to gender and gestational age (full term and preterm). Correlations have been calculated between AUC-E2and birth weight (expressed as % from expected weight) for all singletons, twins both preterm (<37 wks and full term deliveries). Overall birth weight was lower than expected for gestational age in almost all subgroups, particularly in singletons compared to twins, preterm compared to full term deliveries and in males compared to females. Although the differences were not statistically significat, the pattern was maintained in all groups. AUC-E2values negatively correlated with birth weight (-0.25 to -0.38). The negative correlation was true for all studied groups. A significant negative correlation was found between AUC-E2attained after COH and birth weight. This may explain for what was previously reported on COH as an independant risk for lower birth weight after infertility treatment. The inevitably supraphysiologic E2 levels associated with COH may lead to low birth weight by an effect on the early development of the placenta and/or an effect on the developing oocyte/embryo. Studies including larger number of live births are needed to confirm or contradict our findings.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)

High frequency of chromosomal abnormalities in embryos obtained from oocyte donation cycles

High frequency of chromosomal abnormalities in embryos obtained from oocyte donation cycles

Supraphysiological estradiol levels do not affect oocyte and embryo quality in oocyte donation cycles.

The study aim was to determine whether supraphysiological estradiol (E(2)) levels reduce oocyte/embryo quality in oocyte donation cycles. A retrospective analysis of 330 consecutive fresh oocyte donation cycles was performed in an assisted reproductive treatment programme between January 1996 and December 2000. Throughout the study period, oocyte donors and recipients followed a standard synchronization regimen that did not vary. A serum E(2) level (peak E(2)) was obtained from all oocyte donors on the morning of HCG administration. Peak E(2) values were grouped by 33rd percentile (group I, <1500 pg/ml; group II, 1500-3000 pg/ml; and group III, >3000 pg/ml). All embryo transfers were performed on day 3 after oocyte recovery. Comparisons between groups revealed no significant differences in the quality of oocytes retrieved, and in fertilization rates. Higher peak E(2) levels were directly correlated with a greater number of oocytes retrieved, embryos available for transfer and cryopreservation, and higher average embryo quality scores (P < 0.005). Compared with group I, group III had significantly higher embryo implantation rates (P < 0.05). Sustained supraphysiological E(2) levels do not adversely affect the quality of developing oocytes and embryos. On the contrary, elevated E(2) levels are associated with a larger number of oocytes and embryos and high-grade embryos for transfer/cryopreservation and, consequently, improved implantation rates.

Controlled ovarian hyperstimulation does not adversely affect endometrial receptivity in in vitro fertilization cycles

Objective: To determine whether exposure of developing endometrium to supraphysiologic E2 levels during controlled ovarian hyperstimulation (COH) in IVF cycles inhibits endometrial receptivity.Design: Retrospective analysis of IVF-ET and ovum donation data.Setting: Tertiary-care teaching hospital.Patient(s): Four hundred ten patients <33 years of age undergoing IVF-ET and 181 anonymous ovum donors (<33 years of age) and their associated ovum recipients.Main Outcome Measure(s): Implantation, pregnancy, and delivery rates.Result(s): Ovarian response to COH (duration of stimulation, peak E2 level, area under the curve for E2 exposure, and number of oocytes retrieved) was similar for IVF-ET patients and ovum donors. Donors were younger than IVF-ET patients (mean age, 27.5 ± 0.2 years vs. 30.4 ± 0.1 years). A similar number of embryos with similar number of blastomeres were transferred in IVF-ET patients and ovum recipients. The fragmentation rate at time of transfer differed slightly between groups (5.2 ± 0.2% vs. 4.3 ± 0.3%). Implantation, pregnancy, and delivery rates did not differ between IVF-ET patients and recipients of donor oocytes.Conclusion(s): Exposure of the developing endometrium to controlled ovarian hyperstimulation during IVF cycles does not inhibit embryo implantation or affect pregnancy and delivery rates.

Vaginal Versus Oral E 2 Administration: Effects on Endometrial Thickness, Uterine Perfusion, and Contractility

Objective: Estrogens play a key role in uterine receptivity by regulating endometrial proliferation and influencing uterine perfusion and contractility. Oral E2 administration is commonly used to prime endometrial receptivity for donor egg IVF-ET and frozen/thawed ETs. Yet, in some cases, endometrial thickness and perfusion appear insufficient, suggesting inappropriate estrogenization. The vaginal route has been proposed for administering drugs targeted to the uterus, because of direct uterine effects (de Ziegler, 1995). Recently, vaginal E2 administration has been shown to achieve higher endometrial tissue E2 levels than oral administration (Tourgeman et al, 1999). Further, high-frequency uterine contractions (UC) at the time of ET may result from incomplete utero-relaxing action of P in the presence of supra-physiologic E2 levels (Fanchin et al, 1999). Hence, looking for an alternate route for E2 priming that could be effective in resistant cases, we compared effects of vaginal or oral E2 administration on endometrial thickness, uterine perfusion, and UC.

Endometrial structure after superovulation: a prospective controlled study

To demonstrate the effect of superovulation using a GnRH agonist (GnRH-a) and hMG and hCG on endometrial structure. Prospective, case-controlled study. Tertiary referral assisted reproduction unit in an academic department. Eleven women undergoing GIFT or IVF, without ET. All women were treated with a long stimulation regimen using the depot GnRH-a Goserelin (ICI, Macclesfield, United Kingdom) and hMG and hCG. Comparison of endometrial biopsy specimens taken 4 days after ovulation in an unstimulated cycle with specimens taken 4 days after oocyte recovery, using standard dating criteria and morphometric analysis. There was no difference in endometrial glandular development as assessed by either standard criteria or morphometric analysis. Superovulation preceded by pituitary down regulation is not associated with abnormal endometrial glandular development, even though supraphysiological levels of E2 and P are induced.

Clomiphene citrate affects cervical mucus and endometrial morphology independently of the changes in plasma hormonal levels induced by multiple follicular recruitment

To analyze the effects of clomiphene citrate (CC) on cervical mucus (CM) and endometrial morphology independently of hormonal changes encountered when CC is administered for ovulation induction. Volunteers whose ovarian functions were temporarily suppressed (n = 18) by a long-acting GnRH agonist and 6 women of similar age suffering from premature ovarian failure (POF) received E2 and P. Half of the women also received CC (50 mg/d, days 2 to 6). Tertiary University Institution, Hôpital A. Béclère. Eighteen volunteers suffering from infertility not related to a uterine cause and 6 women of similar age suffering from POF. Plasma gonadotropins, E2, and P were measured at baseline to confirm that the ovaries were inactive and twice weekly during physiological E2 and P replacement. Cervical mucus was analyzed on day 14 and scored from 0 to 15. Endometrial biopsies were obtained on replacement days 20 and 24 for conventional histology and immunocytochemistry analysis of estrogen receptors and progesterone receptors (PR). Premature ovarian failure women whose results have been previously published served as controls for day 20 biopsies. Cervical mucus scored lower in women who received CC (5.5 +/- 3.2) than in controls (13.6 +/- 4.7, mean +/- SEM). On day 20, endometrial findings were similar in women treated with CC and in controls. On day 24, specimens showed a significant delay in endometrial maturation in women treated with CC. On day 24, only staining for PR selectively persisted in endometrial stroma, and no difference was observed between women who received CC and controls. Our results indicate that CC significantly alters CM quality and late luteal phase endometrial morphology despite physiological levels of plasma E2 and P. Hence, clinicians should monitor E2 levels when using CC, and caution should be exerted when supraphysiological levels of E2 are not present to counterbalance the effects of CC on the CM and the endometrium.

Up-regulation of the uterine estrogen receptor and its messenger ribonucleic acid during the mouse estrous cycle: the role of estradiol.

Uterine estrogen receptor (ER) and ER mRNA were measured in cycling and ovariectomized (OVX) estrogen-treated mice to probe the physiological regulation of the intracellular distribution and biosynthesis of ER. On proestrus, when plasma estradiol (E2) levels are highest, the cell nuclear ER concentration was 2.4-fold greater than on metestrus. This increase was primarily attributable to an increase in total cellular ER (cytosolic plus nuclear ER) and only secondarily to an activation of ER, as measured by its redistribution from the cytosolic (i.e. nuclear-extractable) to the nuclear (nonextractable) fraction. Total cellular ER concentration was 1.8-fold higher on proestrus than on metestrus, whereas the fraction of total ER in the nuclear compartment (i.e. the percentage activated) was only 1.3-fold higher. The concentration of cellular ER mRNA was 3-fold greater on proestrus than on the other days of the estrous cycle, suggesting that the increased concentration of ER on proestrus was a consequence of increased ER gene expression. In OVX mice, physiological and, to a lesser extent, supraphysiological levels of E2 increased cell nuclear ER. As in proestrous mice, the increased ER content contributed more than ER activation to the increased cell nuclear ER concentration. Physiological, but not supraphysiological, concentrations of E2 increased ER mRNA in OVX mice. Together, these results suggest that up-regulation by E2 of ER mRNA and ER accounts for most of the increased nuclear binding of ER on proestrus. E2-dependent activation and consequent DNA binding of ER presumably initiate this process, but quantitatively account for only a small fraction of the increased nuclear binding of ER.

Aging and chronic estradiol exposure impair estradiol-induced cornification but not proliferation of vaginal epithelium in C57BL/6J mice.

Long-term exposure of adult female rodents to estrogen has many deleterious effects on reproductive neuro-endocrine structure and function, but its effects on peripheral target tissues are not well known. This study was designed to determine whether chronic exposure of young mice to estradiol (E2) alters the response of the vagina to E2, and if so, whether aging potentiates this alteration. Eight-week-old mice were ovariectomized (ovx) and given subcutaneous Silastic or polyethylene (PE) implants containing E2. Silastic implants produced supra-physiologic E2 levels, while E2 levels in PE-implanted mice were within the physiologic range. Initially all E2-exposed mice showed vaginal cornification (CORN). However, CORN soon began to decline and was virtually absent 3-5 mo after implantation, despite evidence of continued, albeit reduced, release of E2 from the implants. Mice were reimplanted with new E2 implants to determine whether the loss of CORN resulted from an altered response to E2 or from a decreased release of E2 from the implants. Vaginas of mice previously exposed to either Silastic (high E2) or PE (low E2) implants failed to cornify in response to new E2 implants, whereas vaginas of mice that had been initially exposed to implants without E2 cornified in response to identical E2 implants. When old (23 mo) acutely ovx mice were given E2-containing Silastic implants, the peak level and duration of CORN were only one-third and one-fifth, respectively, of that seen in young mice. Non-cornifying epithelia from both young and old chronically E2-exposed mice were as hyperplastic and active mitotically as cornifying epithelia, indicating that the loss of CORN was not a result of decreased epithelial proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)