Ovarian hyperstimulation syndrome associated with the use of the gonadotropin-releasing hormone agonist leuprolide acetate.

Severe ovarian hyperstimulation syndrome occurred after the administration of LA to suppress multicystic ovaries. It is possible that this patient with multiple ovarian cysts, each 2 to 3 cm in size, is at increased risk for a paradoxical stimulatory rather than inhibitory response to GnRH-a.

Correlation between puberty and the development of autoimmunity to spermatozoa in men with cystic fibrosis.

OBJECTIVE: To test the hypothesis that puberty is a necessary factor in the pathogenesis of autoimmunity to sperm in men with cystic fibrosis (CF), we studied prepubertal and postpubertal males with CF versus an age-matched group of males with type 1 diabetes as controls. DESIGN: Sera from CF and diabetic males treated at University Hospital, State University of New York, Stony Brook, were tested by indirect immunobead binding for antisperm antibodies and by radioimmunoassay for testosterone (T), luteinizing hormone, and follicle-stimulating hormone. The finding of autoantibodies to spermatozoa was correlated with chronological age, as well as with clinical and hormonal pubertal status. RESULTS: Autoimmunity to sperm, as detected by humoral antisperm antibodies, was documented solely in postpubertal males, as judged by hormonal and clinical criteria. Eighty-three percent of sexually mature CF males and 6.3% (1 of 16) diabetic males exhibited autoantibodies to sperm. These antibodies were only detected when serum T levels were > 8.7 nmol/L (250 ng/dL). CONCLUSIONS: These results suggest that puberty, and presumably, active spermatogenesis is a requirement for the development of autoimmunity to sperm in men with CF.

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.

Serum follicle-stimulating hormone inhibition is a marker for preovulatory oocytes in in-vitro fertilization and embryo transfer.

A retrospective analysis was performed on 64 cycles stimulated with human menopausal gonadotrophin and/or pure follicle-stimulating hormone (FSH) and oestrogen (E2) levels. The increase in serum E2 on the day of HCG administration did not correlate (r = 0.05) with the number of preovulatory oocytes (preovs) or with an increase or decrease in serum FSH (r = 0.31). However, the change in serum FSH showed a significant correlation with the number of preovs (r = -0.95, P = 0.013). The probability of obtaining two or more preovs was relatively greater (1.47x) than that of other IVF patients, when there was a drop in FSH of 5% on the day of human chorionic gonadotrophin administration.

Hormonal manipulation of endometrial maturation.

Three experimental protocols were devised to induce endometrial maturation in 12 women with ovarian failure. Each was planned to serve a dual purpose: to resolve a particular clinical situation related to synchronization between ovum donor and recipient and to answer a specific question about endometrial physiology. A fourth protocol of sequential estrace (2-6 mg/day) and progesterone (P4; 25-50 mg/day, im) simulating the 28-day natural cycle, served as a control protocol (18 cycles). A short follicular phase protocol consisted of only 6 days of estrogen (E) administration before addition of P4 (13 cycles). In the long follicular phase protocol (5 cycles), estrace was given for 3-5 weeks, and P4 administration was accordingly postponed. In 6 accelerated secretory transformation cycles, 150 mg/day P4 were administered, im, from day 15 onward. The adequacy of the induced endometrial cycles was evaluated by hormonal, morphological, and histochemical criteria relevant to endometrial normalcy and receptivity. Serum estradiol levels and the areas under the estradiol curves for the long and short follicular phase protocols differed significantly from those during the control cycles (P less than 0.005). Areas under the estradiol curves in the accelerated secretory transformation protocol yielded significantly higher P4 values than those in all other protocols (P less than 0.05). All biopsies in the 3 experimental protocols compared favorably with those of the control protocol. Glycocalyx intensity (periodic acid-Schiff) and the amount of galactose residues in the glycocalyx (Ricinus communis-I agglutinin) were greatest during the periimplantation interval. We conclude that a very short exposure of the human endometrium to E or, conversely, prolonged E stimulation will allow normal endometrial maturation with the addition of P4. Supraphysiological doses of P4 in the accelerated secretory transformation protocol significantly enhanced endometrial maturational processes.

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.

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)

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.

Distribution of T cell subsets in follicular fluid.

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.

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 less than 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 less than 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.

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.

Effect of advancing pregnancy on the glucose tolerance test and on the 50-g oral glucose load screening test for gestational diabetes.

To determine the validity of the 50-g, one-hour glucose screening test for gestational diabetes in relation to the duration of pregnancy, 101 patients from a high-risk population had the screening test in the first trimester and glucose tolerance tests (GTT) in the second and third trimesters. The sensitivity (88%) and specificity (82%) of the screening test were similar to values reported when the test is performed later in pregnancy. However, immediate follow-up GTTs in the second trimester revealed only 25% instead of 88% of the gestational diabetic patients uncovered by the positive screening tests. Guidelines for screening for gestational diabetes should include follow-up with a third-trimester GTT on all patients who have positive screening tests even in the presence of normal follow-up second trimester GTTs.