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A critical aspect of human in vitro fertilization (IVF) treatment programs is the timing of human chorionic gonadotropin (hCG) administration to induce final oocyte maturation. Patients were treated with clomiphene citrate (Serophene, Serono Laboratories, Inc., Randolph, MA), 100 mg, and human menopausal gonadotropin (Pergonal, Serono Laboratories, Inc.) 1 ampule daily from cycle days 4 through 8. The baseline estradiol (E2) level was determined by averaging the E2 values from cycle days 3 and 4. The first day of E2 rise was defined as the day that the E2 level exceeded 150% of the baseline. In general, 5000 IU of hCG (Profasi-HP, Serono Laboratories, Inc.) was administered on the evening of the sixth day of E2 rise. Significantly fewer oocytes were recovered per patient when the hCG was administered on the seventh day of E2 rise, compared with the fifth or sixth day. The recovered oocytes in the seventh-day E2 group had a significantly lower fertilization rate, compared with the other groups. The use of E2-rise days proved to be a simple, successful technique for the timing of hCG administration in an IVF treatment program.

Patients beginning an in vitro fertilization (IVF) treatment cycle were prospectively randomized in double-blind fashion to receive either follicle-stimulating hormone (FSH) (Metrodin, Serono Laboratories, Inc., Randolph, MA) (n = 50) or human menopausal gonadotropin (hMG) (Pergonal, Serono) (n = 48) in combination with clomephene citrate (CC) (Serophene, Serono). There were no statistically significant differences in the percentage of dropped cycles, follicular response as measured by serum estradiol or ultrasound imaging, cycle day for hCG administration, number of oocytes recovered, fertilization and cleavage rates of the recovered oocytes, or the rate of clinical pregnancy establishment. In conclusion, there were no clinically important differences between FSH and hMG when combined with CC for enhanced follicular recruitment for IVF. Therefore, there is no apparent justification for the use of FSH in CC combination regimens, considering FSH's increased cost as compared with hMG.

None of the procedures utilized in human IVF are unique or technically very difficult to perform. However, when considering the nature of the material being handled, it is essential that all laboratory procedures, equipment, and supplies are optimal for IVF . The individuals handling the gametes and embryos must be suitably trained and experienced in handling mammalian gametes and embryos before working with human tissues. In addition, the technologists must be trained in proper tissue culture techniques. Above and beyond the training and experience of the technologist, it is necessary that all laboratory equipment and chemicals for medium preparation be of the highest quality and known consistency, and that periodic checks of the culture conditions be performed using the bioassay of mouse embryos. The functioning of the equipment must be constantly monitored and backup systems be in place wherever possible in order to minimize the chances that laboratory accidents will result in loss or damage of the embryos. Meticulous attention to all aspects of the laboratory procedures will result in the patient's having the best possible chance to obtain a pregnancy.

When clomiphene citrate is used for enhanced follicular recruitment in an in vitro fertilization and embryo transfer program, the usual dosage is 150 mg/day, although we recently reported comparable follicular development (size and number) with 50 mg/day. The present report compares circulating hormone levels between groups of patients receiving the two regimens. Gonadotropin levels were higher in the 150-mg group throughout the follicular phase. Serum estradiol (E2) levels, expressed either as total E2 or E2 per follicle greater than or equal to 15 mm, were also higher throughout the follicular phase in the 150-mg group. During the luteal phase, the progesterone levels were similar in both groups. However, there were higher E2 levels in the 150-mg group during the entire luteal phase. Even though there were no significant differences between groups with regard to the degree of enhanced follicular recruitment, there were significant differences in the observed hormone levels.

Clomiphene citrate (CC) (150 mg/day) is used in most clinical in vitro fertilization and embryo transfer (IVF-ET) programs to induce maturation of several preovulatory follicles rather than the one characteristic of the unstimulated cycle. This study examines whether a reduced dosage of CC will induce the maturation of a similar number of follicles. The advantage of the reduced dosage should be a decrease in the dose-dependent antiestrogenic effects of CC. Normally ovulating women undergoing treatment in an IVF-ET program received CC on cycle days 5 to 9. Thirty-six patients received 150 mg/day, and 60 patients received 50 mg/day. There were no significant differences between the groups in the number or the size of follicles as measured by ultrasonography on the day of human chorionic gonadotropin administration. All seven clinical pregnancies were in the 50 mg group (P less than 0.05). These data suggest that there is no advantage to the 150 mg/day dosage of CC as compared with 50 mg/day with respect to enhanced follicular recruitment, and the higher dosage may have a detrimental effect on pregnancy establishment.

In an attempt to improve the pregnancy rate following in vitro fertilization and embryo transfer by increasing the numbers of embryos available for transfer to each patient, a prospective, randomized comparison of clomiphene citrate alone (50 mg/day, cycle days 5 to 9) with the combination of clomiphene as above plus human menopausal gonadotropin (2 ampules/day, cycle days 6, 8, and 10) was undertaken from January through April 1983, with 17 patients in each group. The combination produced increased follicular development, compared with clomiphene alone, resulting in the retrieval of more fertilizable oocytes. Two clinical pregnancies resulted in each group. These results show that a fixed combination of clomiphene and human menopausal gonadotropin produces a greater degree of enhanced follicular recruitment, resulting in the recovery of an increased number of fertilizable oocytes. The lack of a statistically significant increase in the number of embryos transferred per patient in the combination group as well as the identical number of clinical pregnancies in both groups suggests that this particular combination of clomiphene and human menopausal gonadotropin offers no advantage over the use of clomiphene alone for enhanced follicular recruitment.

We compared fertility potential measurements by the zona-free hamster egg bioassay with the in vitro fertilization of human eggs. Sperm from 24 husbands participating in an in vitro fertilization-embryo transfer program were used in 27 inseminations of the wives' eggs and in simultaneous inseminations of hamster eggs. In seven cases, a positive fertility assessment was obtained in the absence of fertilization of the wives' eggs attributable to egg immaturity or in one case to equipment failure. In the remaining 20 cases, at least one egg was fertilized, for a level of 73%. In 90% of the husbands who fertilized their wives' eggs, a positive fertility assessment was obtained. Two husbands gave false-negative assessments. To account for these, alternative culture conditions were examined; sperm exposure to longer preincubations or at higher concentrations usually improved assessments. These results indicate that fertility assessment with this bioassay is highly correlated with the fertilization of human eggs in vitro.

Prolactin levels during a gonadotropin-induced pregnancy have not been previously reported. A patient with Forbes-Albright syndrome is described. She received radiation therapy, with cessation of her galactorrhea, but she remained amenorrheic. Three years after irradiation, a pregnancy was successful induced with human menopausal gonadotropins and human chorionic gonadotropin. Prolactin levels determined prior to gonadotropin therapy, during an insulin hypoglycemia stimulation test, serially during pregnancy, and postpartum during lactation are presented. These levels are compared with the previously reported levels for basal prolactin, response to insulin hypoglycemia, pregnancy, and lactation. Possible etiologies for the abnormal values and responses obtained from investigation of this patient are discussed.

Polyzoospermia is a rare cause of male infertility. In our clinical practice, patients with exceedingly high sperm counts (ranging from 650 million/ml to 1.75 billion/ml) have invariably been found to have associated poor sperm motility and poor sperm migration in postcoital tests, although the sperm appear morphologically normal. Cases of two infertile couples are presented in which each husband had sperm counts greater than 1 billion/ml. Two methods are reported for the successful management of their infertility problems: (1) precoital dilutional douching and (2) in vitro seminal fluid dilution with 5% dextrose-Ringer's lactate solution and artificial insemination homologous. Each method resulted in improved sperm motility, postcoital tests, and pregnancy.

Stromal cells derived from proliferative or secretory human endometria, cultured in the absence of steroid hormones, grew as monolayers that showed only occasional areas of immunoreactive fibronectin and did not produce detectable levels of prolactin (PRL) or laminin. Treatment with physiological doses of estradiol and progesterone induced PRL production and stimulated cell proliferation, resulting in multilayering with an increase of the saturation density. Electron microscopy showed the development of gap junctions, whereas immunofluorescence revealed a dense pericellular matrix containing fibronectin and laminin. These findings show that human endometrial stromal cells in culture respond to physiological doses of ovarian hormones with ultrastructural, proliferative, and biochemical changes that are characteristic of decidualization in vivo. This culture system thus provides an in vitro model for human decidualization.

In an attempt to maximize the success of in vitro fertilization (IVF) and embryo transfer (ET) as a treatment for human infertility, we have examined the relationship of follicular size and number to the rates of oocyte recovery, fertilization, cleavage, and ET in clomiphene citrate-stimulated cycles. The recovery of oocytes from follicles less than 20 mm in diameter was significantly reduced over that from larger follicles, and those oocytes that were obtained from smaller follicles showed a significantly lower rate of fertilization and cleavage. In addition, the overall chance that a patient would undergo ET was greater in a cycle in which more than one follicle 20 mm or larger was developing than in a cycle in which a single large follicle was developing. This latter observation suggests that attempts at laparoscopic oocyte retrieval should be confined to cycles in which more than one accessible large follicle is developing, thereby maximizing the success rate while minimizing the risk and expense for the patient.

Physicians who intend to perform in vitro fertilization--or the newer alternative, in vivo fertilization and embryo transfer--should be aware of the plethora of laws that potentially cover their work. In perhaps no other area of medicine are there so many separate statutes and regulations that potentially apply. State fetal research laws, abortion statutes, human subject protection laws, and specific in vitro fertilization statutes can determine whether and how the procedure can be undertaken. When donor gametes or a surrogate carrier is used, additional laws governing artificial insemination, paternity, or adoption may come into play to determine the child's legal status and its relationship to the parties involved. This article is designed to guide physicians through the legal maze.

Progesterone (P) has been shown to have potent antiinflammatory and immunosuppressive properties. Previous reports have suggested that the use of P decreases postoperative adhesion formation. To further evaluate the role of pharmacologic doses of progestogens in adhesion prevention, 42 mature New Zealand White rabbits underwent standardized injuries to the uterine horns, fimbriae, and pelvic peritoneum and received one of six treatments. Group S had intraperitoneal placement of normal saline (0.9%); group H received intraperitoneal placement of 32% dextran 70; group IM-P received intramuscular P-in-oil 10 days before and after laparotomy in addition to intraperitoneal saline; group IP-P had intraperitoneal placement of an aqueous P suspension; group DP received medroxyprogesterone acetate intraperitoneally; and group C received no intramuscular or intraperitoneal adhesion-prevention agents. The animals were sacrificed 6 weeks after laparotomy, and the adhesions were scored. Intraperitoneal saline (group S) significantly reduced the amount of adhesions when compared with the control group (C) (P less than 0.05). No significant difference was observed when group S was compared with group H. Intramuscular P added to saline (group IM-P) did not cause further reduction in adhesions when compared with group S. Both group IP-P and group DP had more adhesions than did group S (P less than 0.01). These data fail to support previous claims regarding adhesion prevention by the use of locally or parenterally administered progestogens.

During a 6-month period, a combination of gamete intrafallopian transfer (GIFT) and in vitro fertilization (IVF) was offered to all couples beginning an IVF treatment cycle in whom the wife had anatomically normal fallopian tubes. It was recommended to these couples that sufficient oocytes be reserved for insemination in vitro to determine whether the husband's spermatozoa could fertilize the wife's oocytes. During this interval, 16 couples underwent the combined IVF-GIFT procedure. All of the IVF-GIFT couples had at least two oocytes inseminated in vitro and at least two oocytes for GIFT. Of the 16 IVF-GIFT couples, only 1 (6.25%) achieved a clinical pregnancy. More important, 50% (8/16) of the IVF-GIFT couples had no oocytes fertilized in vitro. With the information concerning lack of fertilization in vitro, appropriate recommendations concerning future fertility management can be made. If the same couples had undergone the GIFT procedure alone, without additional oocytes fertilized in vitro, this information would not have been obtained.

Ultrasonic techniques have been developed as alternatives to conventional laparoscopic aspiration for oocyte retrieval for in vitro fertilization (IVF). Given the advantages (less risk, lower cost, and greater patient acceptance) of these alternative techniques, it is appropriate to assess their efficacy compared with traditional laparoscopic retrieval. This article examines the recovery rate of oocytes and their subsequent fertilization rate with the use of an ultrasonic endovaginal transducer with fixed needle guide and compares these results with other retrieval methods. Comparisons were made between laparoscopic harvesting (n = 71, group I), ultrasonic transabdominal transvesical (n = 21, group II), and ultrasonic vaginal transducer (n = 76, group III). The data demonstrate comparable success using an ultrasonic endovaginal transducer with fixed needle guide. The authors believe this technique to be the procedure of choice for all routine oocyte retrievals during IVF treatment.

The authors' program for matched, anonymous oocyte donation has resulted in two successful pregnancies among the first eight oocyte recipients. All oocyte recipients to date have had ovarian failure or absence with premature ovarian failure the most common cause. All recipients were cycled on a program of incremental oral micronized estradiol and intramuscular progesterone-in-oil. Thirteen candidates for oocyte donation were screened to obtain 8 donors. One donor candidate was excluded because of her medical history. The psychological screening of 2 of the other donor candidates (who subsequently did not complete the donation cycle) revealed a primary motive of financial gain. In general, the psychological profiles of donor candidates revealed a high incidence of troubled families and either reproductive loss or loss of a parent. Ovarian stimulation of the donors followed our standard in vitro fertilization protocol. The recipients' exogenous steroid replacement continued until days 97 and 101, respectively, of the two gestations. Both pregnancies resulted in the delivery of normal singleton males--the first at 40 weeks, the second at 35 weeks.