Glen E. Hofmann

INTERCYCLE VARIABILITY OF DAY 3 FOLLICLE-STIMULATING HORMONE LEVELS AND ITS EFFECT ON STIMULATION QUALITY IN IN VITRO FERTILIZATION

Prior studies have demonstrated that gonadotropin stimulation quality and pregnancy rates are better in in vitro fertilization (IVF) patients with low basal cycle day 3 follicle-stimulating hormone (FSH) levels. The records of 81 patients who had undergone three or more IVF attempts during a 2-year period were studied to determine the degree and potential impact of intercycle variability in basal FSH concentrations. The mean of the individual standard deviations for all 81 patients was 4.2 +/- 0.4 mIU/mL. However, the patients with a mean basal FSH of less than 15 mIU/mL had a mean deviation of only 2.6 +/- 0.2 mIU/mL, whereas those with a mean basal FSH of greater than or equal to 15 mIU/mL had a mean deviation of 7.3 +/- 0.7 mIU/mL. Intercycle variability in basal FSH values did not predict changes in ovarian response to gonadotropin stimulation and thus may not be used to select an optimal cycle in which to stimulate an individual patient. Furthermore, patients with large intercycle variation responded poorly to gonadotropin stimulation independent of their basal FSH concentration. This information allows more precise counseling of patients regarding their appropriateness for assisted reproduction.

Embryo quality and pregnancy rates in patients attempting pregnancy through in vitro fertilization

Patients at low risk for producing abnormal gametes produce a wide range of embryo qualities that correlate well with PRs. These data may be useful in counseling patients and in reviewing treatment and laboratory protocols.

High-dose follicle-stimulating hormone (FSH) ovarian stimulation in low-responder patients for in vitro fertilization.

Follicle-stimulating hormone (FSH) was used in high doses (6 ampoules/day:6FSH) for ovarian hyperstimulation for in vitro fertilization in women with a previous voor response to stimulation with the equivalent of “4FSH.” Luteinizing hormone levels did not differ between stimulations, but both FSH and estradiol levels were higher in the 6FSH compared to the 4FSH cycle. There were fewer cancellations in the 6FSH cycle, but similar numbers of preovulatory oocytes were retrieved, fertilized, and transferred. The pregnancy rates per attempt and retrieval were higher in the 6FSH cycle. We conclude that raising and maintaining FSH levels during stimulation in low responders reduced cancellations and may improve in vitro fertilization outcome.

Correlation of follicular diameter with oocyte recovery and maturity at the time of transvaginal follicular aspiration

Forty-four consecutive patients undergoing transvaginal follicular aspiration for in vitro fertilization underwent ultrasonic measurement of follicular diameter at the time of oocyte retrieval to determine the correlation of follicular size with recovery rates and oocyte maturity. Based on the results of 412 follicles aspirated, the data were grouped by size (≤11, 12–14, 15–17, 18–20, and ≥21 mm) and oocyte maturity. Recovery rates were significantly higher in 18- to 20-mm follicles (P<0.01) and lower in those ≤11 mm (P<0.001). The probability of retrieving a metaphase I or II oocyte was significantly lower in follicles ≤11 mm (P<0.001), somewhat higher in 12- to 14-mm follicles (P<0.01), and equally high among the other groups. There were no differences in the incidence of fractured zonas. We conclude that follicles ≥15 mm provide the highest probability of retrieving mature oocytes and the low recovery rates of mature oocytes from follicles ≤11 mm suggest that, in selected circumstances, the operating surgeon may choose not to aspirate them.

Relationship between circulating human chorionic gonadotropin levels and premature luteinization in cycles of controlled ovarian hyperstimulation.

OBJECTIVE To determine if premature luteinization (serum P levels > 1.1 ng/mL on or before the day of hCG administration) during controlled ovarian hyperstimulation (COH) is associated with elevated levels of serum hCG. SETTING Tertiary fertility center. DESIGN Retrospective evaluation of ovum donors undergoing COH. PATIENTS Forty-four women underwent COH. Comparisons of serum hCG levels and hormonal and cycle characteristics were made between cycles with premature luteinization (group I) and without premature luteinization (group II). RESULTS Group I (16 women) were similar to women in group II in age, amount of hMG, and the ratio of FSH:hMG received. Both groups received hCG on similar days, but women in group I had higher peak E2 levels. Serum hCG levels increased and correlated with serum P levels in group I only and were higher on the day of hCG administration (group I 1.8 +/- 0.9 mIU/mL versus group II 1.2 +/- 0.45 mIU/mL; conversion factor to SI unit, 1.00). Peak E2 and LH levels, ampules of hMG and the FSH:LH ratio, and day of hCG administration did not correlate with hCG levels. Human chorionic gonadotropin exposure, as measured by area under the curve, was significantly higher in group I compared with group II. CONCLUSION Higher serum levels of hCG and integrated hCG exposure are found in COH cycles with premature luteinization compared with cycles without premature luteinization. Higher hCG levels may be due to decreased clearance of hCG from the circulation and/or the hCG content of hMG.

Evaluation of the reproductive performance of women with elevated day 10 progesterone levels during ovarian reserve screening

OBJECTIVES To evaluate the relationship of elevated day 10 P levels (> or = 1.1 ng/mL, conversion factor to SI unit, 3.18) during ovarian reserve screening and reproductive performance. DESIGN Prospective screening with longitudinal follow-up. INTERVENTIONS One hundred seven women underwent ovarian reserve screening with a clomiphene citrate challenge test. MAIN OUTCOME MEASURES Serum FSH, LH, and E2 levels were determined on cycle day 3 and FSH, LH, and P levels were determined on day 10. A fertility evaluation was completed and a treatment plan was instituted. RESULTS Twenty-two of 107 (20.6%) women had day 10 P levels > or = 1.1 ng/mL. Women with elevated day 10 P levels were similar in age to women with normal day 10 P levels (< or = 0.9 ng/mL) but had significantly shorter menstrual cycles, higher day 3 and day 10 FSH levels, higher day 3 E2 levels, and higher day 10 LH levels than women with normal day 10 P levels. During ovarian hyperstimulation, women with elevated day 10 P levels required more ampules of hMG, had lower peak E2 levels, and had fewer mature follicles than women with a normal day 10 P level. Sixteen of 85 (18.8%) women with normal day 10 P levels became pregnant, but none of the 22 women with elevated day 10 P levels became pregnant. The incidence of diminished ovarian reserve was higher in women with elevated day 10 P levels (13/22; 59%) when compared with women with a normal day 10 P levels (9/85; 10.6%). CONCLUSIONS Elevated day 10 P levels (> or = 1.1 ng/mL) during ovarian reserve screening is associated with diminished ovarian reserve and correlates with menstrual cycle parameters associated with a short follicular phase and poor reproductive performance.

A prospective randomized comparison of single- and double-lumen needles for transvaginal follicular aspiration

Patients undergoing ultrasound-directed transvaginal follicular aspiration in a large in vitro fertilization (IVF) program were randomized for retrieval with either a single-lumen needle (SLN;N=22) or a double-lumen needle (DLN;N=22) to compare recovery rates and the technical aspects of their use. Two hundred ten and two hundred two follicles were aspirated with each needle, respectively. Follicular diameters were measured ultrasonically at the time of aspiration and recorded. One or more washes were performed when using the DLN and the SLN was withdrawn each time to recover the fluid in the dead space of the needle. The distribution of follicular sizes was the same for both needles. Oocyte recovery rates (SLN=65.7%; DLN=63.9%) and the incidence of fractured zonae (SLN=9.1%; DLN=6.4%) were the same for both needles (α>0.50; β<0.01). Although there were no differences between the two needles in the number of oocytes provided for IVF, there were technical differences. The DLN needle was more flexible and frequently deviated from the projected path as observed by ultrasound. The SLN may be preferable because it is technically easier to use; however, there may remain specific indications for the use of the DLN.

Evaluation of the significance of the estradiol response during the clomiphene citrate challenge test

OBJECTIVE To evaluate the relationship between the E2 response during the clomiphene citrate (CC) challenge test and ovarian responsiveness to exogenous gonadotropins. DESIGN Performance of a CC challenge test followed by ovulation induction with exogenous gonadotropins as part of participation in an assisted reproduction program. SETTING Assisted reproduction program in a large military tertiary care center. PATIENTS Two hundred forty-seven women between the ages of 24 and 39 years with normal CC challenge tests within 1 year of their assisted reproduction cycle. INTERVENTIONS Performance of CC challenge tests and ovulation induction with exogenous gonadotropins as a component of an assisted reproduction cycle. MAIN OUTCOME MEASURES Correlation of the E2 response during the CC challenge test and peak E2, the duration of stimulation, number of ampules of exogenous gonadotropins, number of mature follicles, number of mature oocytes recovered, and fertilization and pregnancy rates in an assisted reproduction program. RESULTS No correlation exists between the E2 response during the CC challenge test and any of the parameters evaluated. CONCLUSION Monitoring of the E2 response during the CC challenge test did not predict ovarian responsiveness or pregnancy rates in patients participating in an assisted reproduction program and one may choose not to include it in routine testing.

Effects of leuprolide acetate on follicular fluid hormone composition at oocyte retrieval for in vitro fertilization

The follicular fluid (FF) in 91 follicles from 17 women treated with leuprolide acetate (LA) before stimulation with gonadotropins for in vitro fertilization were analyzed for estradiol (E2), progesterone (P), androstenedione, prolactin, and human chorionic gonadotropin (hCG) and compared with the concentrations in 128 follicles from 31 women treated with gonadotropins alone. The FF E2 concentration in LA-treated patients was significantly lower than in non-LA patients for all oocyte maturational stages. Follicles containing metaphase II oocytes had significantly lower concentrations of P and hCG in LA-treated patients. These differences persisted when analysis was limited to follicles whose oocytes fertilized normally. These data indicate that in the presence of LA, normal oocyte maturation can occur despite lower intrafollicular concentrations of E2 and P.

Immunohistochemical localization of epidermal growth factor receptor during implantation in the rabbit

Epidermal growth factor receptor was localized immunohistochemically during implantation (gestational days 7 through 14) in the rabbit. During early implantation (days 7 through 9), immunostaining was observed in the cytoplasm and on the surface of the syncytiotrophoblastic knobs. By day 8, immunoreactivity was most pronounced in knobs interacting directly with uterine epithelium but was noted in nonknob cytotrophoblast as well. Fetal membranes, identified by day 10, were stained intensely on all days examined. In later gestation the trophoblast was stained intensely on the surface and in the cytoplasm, with some staining over nuclei. No appreciable changes in the staining pattern were observed after day 10. Uterine epithelium demonstrated epidermal growth factor receptor staining first on the antimesometrial (day 7) and then the paraplacental epidermal (day 9). After day 10, most staining was at the embryo-maternal interphase. These data suggest that the embryo and uterine epithelia can receive signals from their environment during and after implantation through the epidermal growth factor receptor.