Kathleen Droesch

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.

Value of suppression with a gonadotropin-releasing hormone agonist prior to gonadotropin stimulation for in vitro fertilization

This study examined the use of gonadotropin-releasing hormone agonist (GnRHa) suppression before gonadotropin stimulation in 26 patients with failed prior in vitro fertilization (IVF) attempts and variable basal serum gonadotropin levels. Leuprolide, 1 mg subcutaneously per day, was administered from the midluteal phase of the cycle before IVF treatment. Concomitantly, stimulation was initiated on cycle day 3 with human menopausal gonadotropin (hMG) and follicle stimulating hormone (FSH). Based on their prior IVF attempts and serum gonadotropin levels on cycle day 3, 9 patients were high responders with elevated mean basal luteinizing hormone (LH)/FSH, 8 were low responders with elevated mean basal FSH/LH, 7 were intermediate responders with normal mean basal FSH/LH and a history of premature LH surge, and 2 had elevated (perimenopausal) mean FSH and LH. Leuprolide was discontinued on the day of human chorionic gonadotropin (hCG) administration. Prior IVF attempts in the same patients with the same protocol, but without GnRHa suppression, were used as controls. The mean number of ampules of hMG and FSH was significantly higher in leuprolide cycles than in controls. The mean day of hCG administration was also higher for leuprolide cycles than for controls. The mean LH and progesterone levels on the day of hCG were significantly lower in leuprolide cycles. The mean number of preovulatory oocytes aspirated and transferred was higher in leuprolide cycles. Cancellation and pregnancy rates were improved in leuprolide cycles. It is concluded that prior GnRHa suppression is beneficial for follicular recruitment for IVF. More patients with variable basal serum gonadotropin levels need to be studied before definite recommendations are made.

Follicular atresia associated with concurrent initiation of gonadotropin-releasing hormone agonist and follicle-stimulating hormone for oocyte recruitment

The ability of gonadotropin-releasing hormone agonist (GnRHa) to cause an initial stimulation of serum gonadotropins was used for follicular recruitment for in vitro fertilization (IVF) in 12 patients with a history of low estradiol (E2) response to conventional gonadotropin stimulation. Stimulation was initiated on cycle day 3 with concurrent administration of leuprolide (1 mg/day subcutaneously) and follicle stimulating hormone (FSH, 4 ampules/day intramuscularly). An 8-fold increase in basal serum luteinizing hormone (LH) and a 4-fold increase in basal serum FSH was seen on cycle day 4. Serum progesterone levels rose significantly by day 6. When compared to prior IVF attempts in these patients, the mean day of human chorionic gonadotropin administration and corresponding E2 levels were not significantly different. More atretic oocytes and fewer preovulatory oocytes were retrieved using GnRHa, and no increase was seen in total oocytes retrieved. One patient was canceled for poor E2 response, and one patient conceived, with a current viable pregnancy. It is concluded that concurrent initiation of leuprolide and FSH stimulation on cycle day 3 in patients with prior low response does not improve oocyte recruitment, and the high LH environment generated from initial stimulation of the agonist may be detrimental to normal oocyte development.

Spontaneous and Pharmacologically Induced Remissions in Patients With Premature Ovarian Failure

To determine the fertility potential of patients with apparent ovarian failure, a retrospective analysis of 86 ovarian failure patients in the Norfolk oocyte donation program was performed. None of the 23 patients with primary ovarian failure ovulated. Seven of 63 (11.1%) with secondary ovarian failure did ovulate, and three of 63 (4.8%) conceived and delivered normal, healthy infants. Of patients whose etiology for ovarian failure was partial ovarian resection or chemotherapy, the ovulation rate and pregnancy rate were 30.8 and 15.4%, respectively, compared with 5.0 and 1.7%, respectively, for the other patients with secondary ovarian failure. Serum estradiol and FSH obtained during hormone replacement were not predictive of the resumption of normal reproductive functions. Therefore, it is recommended that patients with secondary ovarian failure, especially in the better-prognosis group, be treated with a trial of estradiol replacement and have close monitoring for ovulation before oocyte donation.

Timing of oocyte retrieval in cycles with a spontaneous luteinizing hormone surge in a large in vitro fertilization program

Forty-four cycles with a spontaneous luteinizing hormone (LH) surge among 377 in vitro fertilization (IVF) patients were studied for outcome with different timing of oocyte retrieval. Mean number of preovulatory oocytes per retrieval and per transfer was significantly less in these cycles than in controls. Mean number of preovulatory oocytes per retrieval and per transfer was significantly higher when the human chorionic gonadotropin (hCG)-retrieval interval was greater than 35 hours, compared with less than 24 hours. In cycles with an hCG-retrieval interval of less than 24 hours, percentage of preovulatory oocytes was higher when serum estradiol (E2) decreased by greater than 15% on the morning after hCG administration compared with a plateau or an increase in serum E2. Timing oocyte retrieval after spontaneous LH surge should consider the hCG-retrieval interval and changes in E2 levels after hCG administration; this may avoid cancellation for many patients.

Laparoscopic gonadectomy for gonadal dysgenesis

Females with a 46,XY karyotype have approximately a 25% chance of developing a malignancy in the dysgenetic gonad. For this reason, it has been recommended that all patients with Y-chromosomal material and dysgenetic gonads undergo exploratory laparotomy and gonadectomy. This report describes laparoscopic adnexectomy in a patient with gonadal dysgenesis

Spontaneous luteinizing hormone (LH) surges are associated with more rapidly increasing estradiol (E2) and follicle stimulating hormone (FSH) in in vitro fertilization and embryo transfer

In a retrospective analysis of 64 patients stimulated with human menopausal gonadotropin (hMG) and/or pure follicle stimulating hormone (FSH); 35 cycles with spontaneous luteinizing hormone (LH) surges were compared with 29 control cycles with respect to serum FSH and estradiol (E2) levels drawn on the day prior to and the day of human chorionic gonadotropin (hCG), approximately 16 hr after gonadotropin stimulation. FSH decreased significantly (P<0.05) in control cycles where two or more preovulatory oocytes (preovs) were obtained, in contrast to cycles with a spontaneous LH surge, where FSH increased irrespective of the number of preovs. The E2 increase in the LH surge cycles was significantly higher (P<0.05) than in the control cycles. However, the increase in E2 did not correlate with the change in FSH levels or with the number of preovs.

Spontaneous and Pharmacologically Induced Remissions in Patients with Premature Ovarian Failure

&NA; To determine the fertility potential of patients with apparent ovarian failure, a retrospective analysis of 86 ovarian failure patients in the Norfolk oocyte donation program was performed. None of the 23 patients with primary ovarian failure ovulated. Seven of 63 (11.1%) with secondary ovarian failure did ovuiate, and three of 63 (4.8%) conceived and delivered normal, healthy infants. Of patients whose etiology for ovarian failure was partial ovarian resection or chemotherapy, the ovulation rate and pregnancy rate were 30.8 and 15.4%, respectively, compared with 5.0 and 1.7%, respectively, for the other patients with secondary ovarian failure. Serum estradiol and FSH obtained during hormone replacement were not predictive of the resumption of normal reproductive functions. Therefore, it is recommended that patients with secondary ovarian failure, especially in the better‐prognosis group, be treated with a trial of estradiol replacement and have close monitoring for ovulation before oocyte donation.

Transdermal estrogen replacement in ovarian failure for ovum donation

This study examined the efficacy of transdermal estradiol (TE2) replacement versus oral estradiol (OE2) through evaluation of peripheral steroid levels, endometrial morphology, and clinical outcome in six patients with ovarian failure. Patients were begun on sequential E2 and progesterone replacement with transdermal E2 patches. Endometrial biopsies were done on day 21 of the first replacement cycle and day 26 of the second cycle. Controls were 28 cycles on a regular 28-day micronized OE2 protocol. No significant difference was found between E2 levels throughout the cycle of the two respective stimulation protocols, except for days 12 to 14, when the OE2 protocol produced significantly lower E2 than did the TE2 protocol (P less than 0.01). A positive, highly significant correlation was found between estrone (E1) and E2 values in the OE2 group (r = 0.92) (P less than 0.003). During OE2 administration, E1 was significantly higher than E2 (P less than 0.01). E1 was not found to be higher than E2 in the TE2 group, resulting in a significant difference in the E2/E1 ratio of 1.59 +/- 1.6 for TE2 compared with 0.13 +/- .04 for OE2 (P less than 0.05). Early biopsies in patients on TE2 revealed glandular components that were dated as day 18.2 +/- 1.7, while the stroma was dated as day 21.8 +/- 0.8, a statistically significant disparity (P less than 0.01). In patients on OE2, the same significant 3-day glandular/stromal disparity was observed (P less than 0.05). Morphologic evaluation of late biopsy specimens revealed day 25.0 +/- 0.8 and 24.5 +/- 1.5 for TE2 and OE2 groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of T cell subsets in follicular fluid**Supported by the Contraceptive Research and Development Project, Eastern Virginia Medical School, under a Cooperative Agreement with the United States Agency for International Development (A.I.D.) grant DPE-2044-A-00-6063-00. The views expressed by the authors do not necessarily reflect the views of A.I.D.

Examination of follicular fluid (FF) from in vitro fertilization patients revealed a significant difference in concentrations of lymphocytes and T cell subpopulations with increased oocyte maturation. A total of 111 follicles containing 82 oocytes were aspirated from 10 patients undergoing laparoscopic oocyte retrieval. FF from 61.3% of the follicles was classified as clear and 38.7% as bloody, based on gross and microscopic appearance. A mean of 1.78 X 10(6) lymphocytes/ml was obtained from peripheral blood (PB) as compared to 2.14 X 10(5) and 2.79 X 10(5) lymphocytes/ml for clear and bloody FF, respectively. There were 6.3 X 10(5) T4 and 3.7 X 10(5) T8 lymphocytes in PB, resulting in a T4/T8 ratio of 1.72, which is not significantly different from that of the general population. The mean concentration of FF T4 and T8 lymphocytes decreased with increased oocyte maturation; the T8 reduction was statistically significant (P less than 0.05). The proportion of T4 to T8 lymphocytes in FF remained unchanged and was unaffected by maturity of the oocyte. Although estradiol (E2) did not vary with oocyte maturity, progesterone (P) increased and E2/P decreased. There was no correlation between E2 or P levels and distribution of T cells. Fertilization rates were higher in more mature oocytes, but there was no correlation between fertilization and E2, P, E2/P, or T cell subpopulations. It remains to be determined what factors result in the decrease in lymphocytes with increased oocyte maturity and the observed difference in FF T4/T8 compared to PB.