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D Navot

Publications and source records attributed to D Navot.

At least 37 records · Page 2Linked to original sources
PubMed1993

Transforming growth factor-alpha in human implantation trophoblast: immunohistochemical evidence for autocrine/paracrine function.

Epidermal growth factor (EGF) and its receptor (EGF-R) have been demonstrated in human implantation sites. Transforming growth factor-alpha (TGF-alpha), a protein with extensive sequence homology to EGF and with equal affinity for the EGF-R, was localized immunohistochemically in early intrauterine and ectopic pregnancies. Within the same experiments, TGF-alpha immunostaining was more intense in ectopic than intrauterine pregnancies. In both groups, TGF-alpha immunostaining was moderate to intense in the syncytiotrophoblast (ST), light to moderate in the cytotrophoblast (CT), and moderate to intense in intermediate trophoblast (IT). In ST, TGF-alpha immunostaining localized to the cytoplasm and plasma membranes, including microvilli. No nuclear associated TGF-alpha was noted in ST. In CT, differential TGF-alpha immunostaining was noted between the villous and nonvillous CT. Villous CT demonstrated light to absent cytoplasmic TGF-alpha immunostaining with intense nuclear staining. In contrast, nonvillous CT revealed moderate to intense cytoplasmic staining without demonstrable nuclear staining. These results demonstrate the presence of immunoreactive TGF-alpha in all forms of trophoblast. The known presence of the EGF-R suggests an autocrine/paracrine role for TGF-alpha during human implantation.

Embryo Implantation↗
PubMed1993

Immunohistochemical localization of transforming growth factor-alpha in human endometrium, decidua, and trophoblast.

Transforming growth factor-alpha (TGF-alpha) was localized immunohistochemically in human proliferative and secretory endometrium, decidua, and trophoblast from first, second, and third trimester pregnancies. In proliferative endometrium, TGF-alpha immunostaining was moderate to intense and localized predominantly to stromal cells, whereas glandular staining was absent to light. After ovulation, TGF-alpha staining was light within the stroma, but moderate to intense around spiral arterioles. Moderate to intense staining was also detected in glandular and surface epithelium in secretory endometrium, with no staining noted in subnuclear vacuoles. In hypersecretory endometrium, staining was predominantly epithelial. In decidua, TGF-alpha was detected in intermediate trophoblast and on the surface epithelium. In first trimester trophoblast, TGF-alpha was detected in both cytotrophoblast (CT) and syncytiotrophoblast. Cytoplasmic staining was light in CT and moderate to intense in ST, with particular staining of plasma membranes. Intense TGF-alpha staining of nuclear membranes in CT was noted. TGF-alpha staining was light to absent in second and absent in third trimester trophoblast. This study demonstrates immunoreactive TGF-alpha in tissues known to be responsive to epidermal growth factor, and also demonstrates the presence of immunoreactive TGF-alpha associated with nuclear membranes. Thus, TGF-alpha may play an autocrine/paracrine role in endometrial development and trophoblast function.

Decidua↗
PubMed1993

A prospective evaluation of clomiphene citrate challenge test screening of the general infertility population.

OBJECTIVE: To assess the results of screening an unselected general infertility population for diminished ovarian reserve with the clomiphene citrate challenge test. METHODS: Two hundred thirty-six couples were followed prospectively and studied for the relationship between clomiphene citrate challenge test screening and final diagnoses and long-term fertility rates. RESULTS: Abnormal clomiphene citrate challenge tests were found in two of 61 (3%) of the patients younger than 30 years, in five of 72 (7%) aged 30-34, in seven of 68 (10%) aged 35-39, and in nine of 35 (26%) aged 40 or older. An abnormal test predicted lower pregnancy rates; conception occurred in 92 of 213 (43%) of patients with normal results, but only two of 23 (9%) of patients with abnormal results (P < .004). Unexplained infertility (not considering the clomiphene citrate challenge test) was a common finding in patients with abnormal clomiphene citrate challenge test results (12 of 23). This incidence was significantly higher than that in patients with normal clomiphene citrate challenge test results (20 of 213) (P < .001). CONCLUSIONS: Approximately 10% of the patients in the general infertility population had abnormal clomiphene citrate challenge tests. The incidence of abnormal results increases with age beginning in the early 30s, occurs with a higher frequency in patients who would otherwise be diagnosed with unexplained infertility, and prognosticates decreased long-term pregnancy rates.

Adult↗
PubMed1992

Angiotensin-I-converting enzyme and its correlation with human follicular fluid steroids.

Angiotensin-I-converting enzyme (ACE) is a peptidyl-dipeptide hydrolase which splits off the dipeptide His-Leu from the decapeptide angiotensin I and thus converts it to angiotensin II. We determined ACE activity in human preovulatory follicular fluid to further establish the intraovarian activity of the renin angiotensin system. Follicular fluids (n = 18) were obtained from eight patients undergoing in vitro fertilization (IVF) and embryo transfer (ET). ACE activity in follicular fluid and serum was determined by fluorescent spectrophotometry. The median follicular fluid ACE activity was 1.12 (range: 0.19-1.56) nmol/min/ml. This value was significantly lower than ACE activity in serum, 1.50 (range: 1.22-1.57) nmol/min/ml (P less than 0.001). In contrast to this 3:4 ratio between follicular fluid and serum ACE when expressed per ml fluid, the values were very similar when expressed per mg of protein: 0.025 vs. 0.023 nmol/min/mg in follicular fluid and serum, respectively. Correlations were sought between follicular fluid ACE activity and both serum and follicular fluid E2 and P4. A highly significant correlation (P less than 0.0005, r = 0.73) was found between ACE activity in follicular fluid and follicular fluid P4. The presence of significant ACE activity in human follicular fluid further supports the local-ovarian activity of the renin angiotensin cascade.

Embryo Transfer↗
PubMed1992

An intact zona pellucida is not necessary for successful mouse embryo cryopreservation.

OBJECTIVE: To determine the developmental potential of mouse embryos that underwent cryopreservation after micromanipulation of the zona pellucida. DESIGN: Gaps were produced in the zona pellucida of mouse oocytes or two-cell embryos by zona drilling with acid Tyrode's solution. Zona-drilled oocytes were fertilized in vitro and cultured to the two-cell stage. Two-cell embryos were frozen, thawed, and cultured to the expanded blastocyst stage. RESULTS: There was no difference in the rate of embryo survival post-thaw (248/318, 77% versus 288/345, 83.4%), or in the rate of development to the expanded blastocyst stage (91/248, 36.7% versus 88/288, 30.6%), between embryos that were zona drilled as oocytes and unmanipulated controls. Similarly, there was no difference in the rate of cryosurvival (206/217, 94.9% versus 168/187, 89.8%) or development to the blastocyst stage (154/206, 74.7% versus 132/168, 78.6%) between embryos that were fertilized in vivo and zona drilled at the two-cell stage and embryos that were unmanipulated. CONCLUSIONS: These findings indicate that small gaps in the zona pellucida, such as those that result from micromanipulation, do not significantly alter the ability of embryos to withstand cryopreservation.

Animals↗
PubMed1992

Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment.

OBJECTIVE: To overview the world literature on ovarian hyperstimulation syndrome (OHSS) and modes of prevention and treatment of OHSS. STUDY SELECTION: All the pertinent literature on OHSS, its prevention, and strategies for treatment were reviewed. PREVENTION: Key to prevention is proper identification of the population at risk, which includes women with either the hormonal or the morphological signs of polycystic ovarian disease, high serum estradiol (E2) before human chorionic gonadotropin (hCG) administration (E2 greater than 4,000 pg/mL), multiple follicular response (greater than 35), younger age, and lean habitus. When a high risk situation is recognized, ovulatory dose of hCG may be reduced, avoided (with cycle cancellation), or substituted by gonadotropin-releasing hormone or its agonist. Luteal support with hCG is to be bypassed. To minimize risk of OHSS, endogenous pregnancy-drived hCG may be eluded by judicious cryopreservation of all embryos. Last, follicular aspiration will allow higher levels of E2 and larger number of follicles to be matured with lesser risk of OHSS than conventional ovulation induction without follicular aspiration. TREATMENT: In-house for the severe and intensive care for the critical form. Meticulous fluid and electrolyte balance using both crystalloids and colloids (albumin) until hemoconcentration abates. Paracentesis is indicated for tight ascites, deteriorating kidney functions, and symptomatic relief. Diuretics may be prudently used once hemodilution is achieved. Dopamine drip may be used as a renal rescue, whereas heparin is indicated for thromboembolic phenomena and surgery reserved for abdominal catastrophies. Therapeutic interruption of an early gestation may be lifesaving when all other measures have failed. CONCLUSIONS: Although severe and critical OHSS may not be completely avoided, early recognition of high-risk factors, judicious prevention schemes, and treatment strategies should reduce the complication and long-term sequelae of this iatrogenic syndrome.

Chorionic Gonadotropin↗
PubMed1992

The impact of embryonic development and endometrial maturity on the timing of implantation.

OBJECTIVE: To gain insight into the peri-implantation period in the human and to answer the question whether timing of nidation is dependent on the stage of embryonic development, endometrial maturation, or a possible dialogue between the two. DESIGN: Seventy-five women underwent embryo transfer (ET) throughout 93 cycles. Thirty-three ETs resulted in viable pregnancies and deliveries. These pregnancy cycles were used for embryonic signal detection. Embryos of identical age were transferred onto hormonally and histologically defined endometria of different maturational stages (days 15 to 19). Human chorionic gonadotropin (hCG) was measured by a hypersensitive chemiluminescence assay in maternal serum every 1 to 5 days to detect the first embryonic signal. RESULTS: Individual linear regressions of hCG versus embryonic age and endometrial maturation were performed on 33 viable pregnancy cycles (r2 = 90.5% to 99.9%, P less than 0.02 to 0.002). First signal detection was restricted to an embryonic age of 7.1 +/- 0.28 (mean +/- SD) days (range 6.6 to 7.4) irrespective of endometrial maturation. The pattern of hCG detection was triphasic, described by a sigmoidal curve with the maximal slope corresponding to an hCG doubling time of 15.9 hours. Embryo transfers on cycle day 19 had a steeper slope of hCG detection than days 15 and 16 (P less than 0.05). CONCLUSIONS: First embryonic signal detection (presumed window of implantation) extends between cycle days 20 and 24. Implantation is dependent on embryonic age and is independent of endometrial maturation within this window. The timing and sigmoidal pattern of hCG detection coincides with structural changes of the implantation bed. The steeper slope of late ETs may represent a compensatory mechanism for late maternal recognition of pregnancy for corpus luteum rescue.

Blastocyst↗
PubMed1992

Epidermal growth factor and its receptor in human implantation trophoblast: immunohistochemical evidence for autocrine/paracrine function.

Epidermal growth factor (EGF) and its receptor (EGF-R) were immunohistochemically localized in trophoblast during human implantation from intrauterine and ectopic pregnancies. EGF immunostaining was absent to light in the cytotrophoblast (CT), light to moderate in intermediate trophoblast (IT), and intense in the syncytiotrophoblast (ST). In ST, EGF immunostaining was found mostly in the cytoplasm; however, staining of the plasma membrane was also noted. Immunostaining for the EGF-R was absent to light in the CT and moderate to intense in the IT. Immunostaining for the EGF-R was intense in the ST, with moderate staining in the cytoplasm and intense staining in the plasma membrane. Staining was most intense on the microvilli of the ST. Additionally, EGF-R immunostaining could be demonstrated on nuclear membranes. The increase in the intensity of the immunostaining for both EGF and EGF-R noted in CT, IT, and ST suggests a differentiated expression of this receptor-ligand system in human trophoblast and provides evidence for an autocrine/paracrine role for EGF in trophoblast function. The presence of this receptor-ligand system during early human implantation strongly supports a role for EGF and the EGF-R in embryo-uterine signalling and the implantation process.

Embryo Implantation↗
PubMed1992

Cryopreservation of semen, oocytes, and embryos.

Human embryo cryopreservation is widely applied by programs of assisted reproductive technology. However, recent surveys have shown that relatively few in vitro fertilization programs in the United States substantially increase their per retrieval delivery rates through cryopreservation. While embryos may be successfully frozen and thawed at a range of developmental stages using several different cryoprotectants, the majority of in vitro fertilization programs use 1,2 propanediol to freeze early (pronuclear four-cell) embryos. Ultrarapid freezing techniques are under continued study; they have not yet been shown to offer any clinical advantage over slow freezing protocols. Although interest in oocyte cryopreservation remains high, experimental evidence shows that cryoinjury to human oocytes results in chromosome sorting defects, reduced fertilization, and compromised embryonic development. Micromanipulation of mammalian oocytes appears to have no deleterious effect on subsequent cryopreservation.

Cryopreservation↗
PubMed1992

Ovarian hyperstimulation and follicular aspiration. Effect on ovulatory function.

The return of normal function of the reproductive axis immediately after hyperstimulation and follicular aspiration is of both physiologic and clinical interest. These cycles may be utilized for the replacement of cryopreserved embryos, for repeated ovarian stimulation or for any alternative treatment that relies upon normal ovulatory function. Thirty-five women were randomly assigned to be monitored in the first (n = 11), second (n = 13) or third (n = 11) menstrual cycle after in vitro fertilization (IVF). Five of 35 patients (14.3%) failed to ovulate, 2 in each of the first and second menstrual cycles and 1 in the third cycle after IVF. Six (20%) ovulatory cycles demonstrated luteal phase deficiencies. The defective luteal phases were evenly distributed between cycles immediately after IVF and those more remote in time from the procedure.

Academic Medical Centers↗
PubMed1991

Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility.

Female fertility declines with advancing age. To establish whether this age-related reproductive failure results from diminished oocyte quality or uterine/endometrial inadequacy we investigated ovum donation in 35 infertile women, aged 40 years or older (mean 42.7 [SE 0.3]) who had failed at attempts at conception with their own (self) oocytes. Oocytes were donated by 29 young individuals (mean age 33.4 [0.7]) undergoing in-vitro fertilisation (IVF). 8 (5.3%) pregnancies were achieved in 150 cycles of ovulation induction with self-oocytes and 2 (3.3%) in 60 such cycles by in-vitro fertilisation (IVF), but none attained viability. By contrast in 50 cycles with donated oocytes 28 (56%) pregnancies and 15 (30%) deliveries were realised (p less than 0.005). The rate of implantation per embryo transferred was higher (14.7%) with donated oocytes than that with self-oocytes (3.3%) (p less than 0.01). To further elucidate the contribution of age to reproductive outcome, pregnancy results were compared between the young donors and older recipients. Both donors and recipients shared oocytes from the same induced cohort. Rates for clinical pregnancy and delivery did not differ between donors (33% and 23%) and recipients (40% and 30%). Our data suggest that the age-related decline in female fertility is attributable to oocyte quality and is correctable by ovum donation. The uterus can adequately sustain pregnancies even when reproductive potential is artificially prolonged into the late 40s.

Adult↗
PubMed1991

The window of embryo transfer and the efficiency of human conception in vitro.

Women with ovarian failure transferred with donated oocytes provide a unique in vivo model for the elucidation of the window of implantation and efficiency of reproduction in the human. Throughout 52 ovum donation cycles, the temporal window of endometrial receptivity was tested by replacing 2- to 12-cell embryos between days 16 and 24 of hormonally and histologically defined cycles. Of 37 transfers within days 17 to 19, 15 (40.5%) conceptions occurred. Twelve (32.4%) have reached viability. Of 11 patients transferred on days greater than or equal to 20, none conceived. Likewise, no pregnancies were achieved with 4 transfers on cycle day 16. Analysis of multiple embryo transfers within the suggested window of endometrial receptivity (days 17 to 19) revealed 14 of 24 (58.3%) to be conception cycles. considering only transfers with two or more embryos, at least one of which is of high quality (grades 1 to 2), yielded a 63.2% pregnancy rate. The results indicate a very high efficiency for in vitro fecundity provided optimal conditions are attained. The concepts leading to success in the ovum donation model should set the course for continued research toward improving results in other forms of assisted reproduction.

Abortion, Spontaneous↗
PubMed1991

Gonadotropin-releasing hormone agonist-induced ovarian hyperstimulation: low-dose side effects in women and monkeys.

OBJECTIVE: To determine whether low (subtherapeutic) doses of gonadotropin-releasing hormone agonists (GnRH-a) can cause ovarian hyperstimulation. DESIGN: The study is in two parts: a preliminary clinical trial of women and a follow-up study in laboratory primates. SETTING: Normal human volunteers were studied in an academic research environment; primates were in a conventional laboratory setting. PATIENTS, PARTICIPANTS: Human volunteers were selected on the basis of apparent normal health. The monkeys were believed to be of normal reproductive status. INTERVENTIONS: Gonadotropin-releasing hormone agonists were administered at subtherapeutic doses. MAIN OUTCOME MEASURES: After observing ovarian hyperstimulation in two of five women receiving low doses of GnRH-a, a study was specifically designed to test the hypothesis that at low (subtherapeutic) doses of GnRH-a the "flare-effect" can be sustained without achieving down regulation. RESULTS: The data in women and monkeys suggest that a highly individualized response to low GnRH-a doses can be manifested as ovarian hyperstimulation. CONCLUSION: Four points of interpretation are offered: (1) that subtherapeutic doses of GnRH-a can cause ovarian hyperstimulation and related sequelae; (2) this may be a unique observation in that, typically, lower doses of medications have a lower incidence of negative side effects; (3) the findings suggest that GnRH-a prescribed in self-administration regimens may be more prone to such problems in noncompliant patients; and (4) the hyperstimulation response of the ovaries to low GnRH-a doses may indicate a new approach to controlled ovulation induction, although wide individualism was found.

Administration, Intranasal↗
PubMed1991

The effect of female antisperm antibodies on in vitro fertilization, early embryonic development, and pregnancy outcome.

STUDY OBJECTIVE: To evaluate the extent to which human in vitro fertilization-embryo transfer (IVF-ET) alleviates immunological infertility. DESIGN: Retrospective. SETTING: In vitro fertilization program. PATIENTS: Thirty-three patients with positive antisperm antibodies undergoing 50 cycles of IVF-ET in which maternal serum was replaced by 5 mg/mL of bovine serum albumin (BSA) comprised the study group. Seventy-one patients with tubal infertility served as controls. In 50 of these, medium was supplemented with 7.5% maternal serum, and 21 were assigned to BSA substitution. RESULTS: Percentage of fertilization in the study group was significantly lower (41 +/- 31; mean +/- SD) than that of controls with maternal serum (77 +/- 15) and BSA (76 +/- 22). Early embryonic quality, as assessed by percentage of cleavage and morphological grading, was found to be inferior in patients with antisperm antibodies. The percentage of advanced embryos (greater than or equal to 4 blastomeres) at the time of transfer was 42 +/- 39 in the study group, compared with 65 +/- 23 and 75 +/- 35 for maternal serum and BSA controls, respectively. Percentage of morphologically favorable embryos (grades 1 and 2 in a 1 to 5 grading system) was 49 +/- 31 in the study group, compared with 78 +/- 35 and 74 +/- 23 for the controls. Percentage of clinical pregnancy was somewhat lower in the study group (12.5%) than in controls with either maternal serum (18%) or BSA (19%). CONCLUSIONS: Antisperm antibodies may have an adverse effect on fertilization and early embryonic development. Female immunological infertility may not be completely alleviated by IVF-ET.

Adult↗
PubMed1991

A human in vivo model for the luteoplacental shift.

OBJECTIVE: To study the onset of early placental steroidogenesis in humans. DESIGN: Ovarian failure patients who were administered a constant dosage of exogenous estradiol (E2) and progesterone (P) during the luteal phase and early gestation and who conceived after transfer of donated oocytes were used to assess serum hormonal changes throughout early pregnancy. SETTING: Hormonally replaced ovarian failure patients undergoing an egg donation program in an academic research environment. PATIENTS, PARTICIPANTS: Nine human volunteers desiring egg donation. INTERVENTIONS: Replacement of E2 and P. MAIN OUTCOME MEASURE: Serum E2 and P concentrations were measured weekly throughout the patients' gestations. RESULTS: Serum E2 and P levels of these patients remained low in early gestation but significantly increased 25 +/- 1.6 and 34 +/- 1.6 days post embryo transfer, respectively. Regression lines of E2 (r = 0.99; P less than 0.01) and P (r = 0.95; P less than 0.005), intersected basal hormonal levels approximately 3 weeks after transfer. CONCLUSION: This estimate of the onset of placental steroidogenesis is equal to the 5th gestational week as calculated by the patients' last menses, approximately 3 weeks earlier than previously reported.

Corpus Luteum↗
PubMed1991

Multiple pregnancies: risk factors and prognostic variables during induction of ovulation with human menopausal gonadotrophins.

Multiple pregnancies still constitute a major and relatively frequent complication of induction of ovulation by human menopausal gonadotrophins (HMG) despite the increasing sophistication of monitoring techniques. In order to define specific variables which may be associated with multiple pregnancies, we have compared 51 multiple pregnancy cycles to 51 consecutive control singleton pregnancy cycles, following HMG induction of ovulation. The aetiology and classification of anovulation, duration of infertility, total amount of HMG utilized per cycle and the duration of stimulation were not associated with an increase in the rate of multiple pregnancy. Basal serum oestradiol levels and its periovulatory pattern were remarkably similar in the singleton and multiple pregnancy groups. The mean age of the multiple pregnancy group (29.4 +/- 4.4 years) was significantly lower than the mean age of the singleton pregnancy group (31.6 +/- 5.3 years) (P less than 0.05). In the multiple pregnancy group, there were significantly more cycles with intermediate sized (15-17 mm). (P less than 0.002), small sized (12-14 mm). (P less than 0.02) and immature follicles (less than 12 mm) (P less than 0.03), at the time of human chorionic gonadotrophin (HCG) administration, as compared with the singleton pregnancy group. Furthermore, a direct linear correlation was observed between the number of intermediate sized follicles and number of implanted embryos. The presence of intermediate sized follicles at the time of HCG administration after HMG induction of follicular maturation is predictive of, and independently associated with, a higher incidence of multiple pregnancy.

Estradiol↗