Jean Philippe Wolf

Noncompetitive antiestrogenic effect of RU 486 in blocking the estrogen-stimulated luteinizing hormone surge and the proliferative action of estradiol on endometrium in castrate monkeys

The noncompetitive antiestrogenic effects of RU 486 were examined using estradiol (E2)-treated ovariectomized monkeys given RU 486, progesterone (P), or both. The E2-induced luteinizing-hormone (LH) surge of control animals was abrogated by P and/or RU 486. Secretory transformation by P was inhibited by RU 486 coadministration. RU 486 alone (1 mg/kg) induced endometrial secretory transformation, but higher doses (5 mg/kg) inhibited proliferation and secretory activity. Thus in the presence of P, RU 486 is antagonistic but, in absence of P, exhibits endometrial progestational effects at low doses and an antiproliferative (antiestrogenic) effect at higher doses. These data encourage continued evaluation of RU 486 as a potential contraceptive agent acting at the pituitary and/or endometrial level.

Progesterone antagonist (RU 486) for cervical dilation, labor induction, ,and delivery in monkeys: effectiveness in combination with oxytocin

A progesterone antagonist (RU 486), combined with oxytocin, was effective in achieving cervical dilation, labor induction, and early delivery in near-term monkeys. Effects of RU 486 included accelerated flow of colostrum and transiently enhanced weight gain in infants. No overt toxicity on fetuses, mothers, or newborns was detected with the use of a single oral dose of 25 mg.

Transplacental passage of a progesterone antagonist in monkeys

The progesterone antagonist RU 486 dramatically increases myometrial contractility of the pregnant uterus, making it a potential adjunctive therapy for labor induction or therapeutic pregnancy termination. Sixteen female cynomolgus monkeys were studied during the second or third trimester of pregnancy. Hysterotomies were performed with the animals under anesthesia, providing access to the intact placental vasculature. RU 486 (25 mg) was injected intravenously into the mothers. Serial blood samples were drawn from the maternal and fetal-placental compartments for a period of 2 hours. RU 486 achieved a gradient equilibrium between the maternal and fetal-placental circulation within 5 minutes, suggesting free passage by simple diffusion. The clearance kinetics of immunoreactive RU 486 are consistent with an open three-compartment system in mother and fetus. The fetal-placental index decreased from 31.2% to 17.8% between the second and the third trimester of pregnancy. There was no acute toxicity of the RU 486 noticed during the experimental course.

Expression of E- and N-cadherin and CD44 in endometrium and hydrosalpinges from infertile women

In this prospective comparative study, compared with fertile control subjects (n = 12), infertile patients with hydrosalpinx (n = 18) had lower E-cadherin and a trend toward decreased N-cadherin H-scores in the endometrium (3.6 ± 0.6 vs. 2.4 ± 0.8 and 0.57 ± 1.0 vs. 0.52 ± 0.5, respectively). In hydrosalpinx, epithelial N-cadherin expression was discontinuous and disappeared in atrophic patches.

Fertilizing ability of sperm with unexplained in vitro fertilization failures as assessed by the zona-free hamster egg penetration assay: its prognostic value for sperm-oolemma interaction**Supported by grant EA 1752 from Direction de la Recherche et des Etudes Doctorales and grant 91006 from Direction de la Recherche Clinique-Assistance Publique

OBJECTIVE To investigate the fertilizing ability of sperm with previous unexplained IVF failure using the zona-free hamster egg penetration assay. DESIGN Three hundred ninety-six tests were performed after multiple IVF failures. In a subsequent prospective study, 38 IVF attempts using the microdrop insemination technique and 81 subzonal inseminations (SUZI) were performed. One hundred thirty-two tests with donor sperm were carried out as controls. PATIENTS Three hundred fifty-two patients who had a minimum of two unexplained IVF failures including at least 10 metaphase II oocytes were included in the study. RESULTS The ability of the patient sperm to bind to hamster oocytes was lower than that of controls. The largest differences were the percentage of oocytes with swollen sperm heads and the mean number of decondensed sperm heads per penetrated oocyte: both were much lower for patients than controls. Patients with a test result nil did not fertilize any oocytes during the SUZI cycles (n = 7; 50 oocytes), and the post-SUZI fertilization rate for patients with a test value < 10% was significantly lower than that of others (5.4 +/- 10.3 versus 23.8 +/- 8.4, respectively). CONCLUSIONS The defect of sperm involved in IVF failures is mainly a reduction of their fusiogenic ability and not their ability to recognize and bind to the oolemma. Patients with a test result < 10% had a significantly reduced post-SUZI fertilization rate. A test score of zero indicates a major and permanent impairment of the sperm fusiogenic ability.