Compensating human subjects providing oocytes for stem cell research: 9-year experience and outcomes.

PURPOSE: Human oocytes are arguably one of the most important cell types in humans, yet they are one of the least investigated cells. Because oocytes are limited in number, the use of high-quality oocytes is almost entirely in reproduction. Furthermore, regulatory hurdles for research on gametes and regulations on funding related to research on gametes present significant obstacles to research and the advancement of reproductive treatments. Here we report the outcomes of the largest compensated oocyte donation program for research in the USA to date, and probably worldwide. METHODS: Women who participated in oocyte donation for research between 2008 and 2017 were contacted in a phone interview and completed a standardized questionnaire. RESULTS: Of 114 participants, 98 oocyte donors completed donation, donating 1787 mature MII oocytes and a total of 86 skin biopsies. Complication rate, including minor complications, of oocyte donation was 8/98, or 8.1%, for which two involved follow-up. Fifty-seven donors answered questions about their experience. Participants were incentivized primarily by money and a desire to help others and reported an overall favorable experience. Most, but not all, human subjects recalled that they had donated for research, and approximately half recalled that their oocytes were being used specifically for stem cell research. CONCLUSIONS: Compensated oocyte donation provides a reliable path to obtaining high-quality oocytes for research and is reviewed favorably by oocyte donors. The continuation of programs that offer compensation for oocyte donation is invaluable to continued progress and advancements in stem cell research and human embryology, and for the advancement of novel reproductive treatments.

Short-term administration of antivascular endothelial growth factor antibody in the late follicular phase delays follicular development in the rhesus monkey.

Indirect evidence in the nonhuman primate and human suggests that angiogenesis and regulators of angiogenesis such as vascular endothelial growth factor (VEGF) may play an active role in cyclic folliculogenesis. Indeed, the follicle selected for maturation and ovulation possesses a denser microvascular network, and VEGF messenger ribonucleic acid and its protein have been identified in granulosa cells of the developing follicle during the mid- and late follicular phases, with a more intense signal in the mature follicle. The objective of this study was to obtain direct evidence in the nonhuman primate for an active role of VEGF in follicular growth and maturation by studying the effect of VEGF-blocking antibodies in this process. After documenting two normal ovulatory cycles, female rhesus monkeys (n = 7) received iv injections of anti-VEGF antibodies (0.5 mg) twice on successive days in the late follicular phase. Three monkeys also received nonspecific goat IgG (0.5 mg) twice on successive days in the late follicular phase. Daily measurements of estradiol, progesterone, LH, and FSH were obtained during the two control cycles, the anti-VEGF treatment and posttreatment cycles, and the IgG treatment cycle. Anti-VEGF antibody administration significantly lengthened the follicular phase in six of seven monkeys to 17.8 +/- 1.7 vs. 10.0 +/- 0.7 and 9.8 +/- 0.6 in control cycles and 10.7 +/- 0.3 days (mean +/- SE) in IgG-treated cycles. The expected late follicular phase rise in estradiol, as documented in the control cycles (day 0, 96.1 +/- 6.0; day 1, 125.5 +/- 20.0; day 2, 165.5 +/- 24.9; day 3, 183.8 +/- 11.0 pg/mL), was interrupted by anti-VEGF antibody treatment (99.3 +/- 5.0, day 0, preinjection control) to 63.3 +/- 12.2 (day 1), 48.5 +/- 8.7 (day 2), and 57.6 +/- 9.0 (day 3). Mean FSH levels were significantly increased by day 2 of anti-VEGF antibody treatment. After a variable delay, estradiol concentrations increased to reach a preovulatory peak in all anti-VEGF-treated animals, followed by ovulation, normal luteal function, and a normal posttreatment cycle. The data clearly demonstrate that short-term inhibition of angiogenesis with an anti-VEGF-blocking antibody during the later growth phase of the dominant follicle interferes with normal follicular development. Persistence of estradiol secretion and delayed resumption of its rise also suggest recovery of the follicle. We conclude that the angiogenic regulator VEGF is a crucial component in the process of follicular growth in the primate.

Normal ovulatory women with polycystic ovaries have hyperandrogenic pituitary-ovarian responses to gonadotropin-releasing hormone-agonist testing.

Women with polycystic ovary syndrome (PCOS) have chronic anovulation and hyperandrogenism and frequently have abnormalities in their lipid profiles and insulin/insulin-like growth factor axis that increase their lifetime risk for cardiovascular disease. Normal ovulatory women may have polycystic ovaries on ultrasonography and yet lack the clinical features of PCOS. To further explore whether ovulatory women without clinical/biochemical hyperandrogenism but with polycystic appearing ovaries (ov-PAO) have subclinical features of PCOS, we prospectively characterized 26 ov-PAO women and matched them by age and body mass index to 25 ovulatory women with normal appearing ovaries (ov-NAO) and to 22 women with PCOS. After an overnight fast, all women had baseline endocrine and metabolic assessments. In addition, a subset of each group of women underwent GnRH-agonist (leuprolide acetate 1 mg s.c.) testing, ACTH stimulation, and an insulin tolerance test (ITT). At baseline, ov-PAO and ov-NAO women had similar endocrine profiles (LH, LH:FSH, androstenedione, and DHEAS). Compared with ov-NAO, 31% of ov-PAO women had reduced glucose responses after insulin (K(itt)), suggesting mild insulin resistance, and 35% had high density lipoprotein levels below 35 mg/dL, a level considered to represent significant cardiovascular risk. After GnRH-agonist, ov-PAO women had response patterns in LH, total testosterone, and 17-hydroxyprogesterone (17-OHP) that were intermediate between ov-NAO and women with PCOS. Ovarian responses were above the normal range in 30-40% of women with ov-PAO. In ov-PAO, peak responses of LH after leuprolide correlated with triglyceride levels (P < 0.05) and peak responses of 17-OHP correlated inversely with Kitt values (P < 0.05). No significant differences were noted with ACTH testing. In conclusion, occult biochemical ovarian hyperandrogenism may be uncovered using GnRH-agonist in ovulatory women with ov-PAO, while adrenal responses remain normal. Subtle metabolic abnormalities may also be prevalent.

Characterization of the testicular abnormality in 5 alpha-reductase deficiency.

The testes of five phenotypic women (from four families) with 5 alpha-reductase deficiency were studied. In one of the patients, the enzyme deficiency was similar in the testis and epididymis and in fibroblasts cultured from the labia majora. In testes from four of the patients, the concentrations of the 5 alpha-reduced steroids dihydrotestosterone and 3 alpha-androstanediol were less than 10% of those in normal subjects. We conclude that the testis is involved in 5 alpha-reductase deficiency. Impaired spermatogenesis was evident in testicular biopsies from all five subjects, and in two, sperm production, as estimated in testicular homogenates, was less than 10% of normal. The extent to which spermatogenic arrest is due to 5 alpha-reductase deficiency or testicular maldescent is not clear.

Utilizing routine sonohysterography to detect intrauterine pathology before initiating hormone replacement therapy.

OBJECTIVE: To assess the utility of performing routine sonohysterography in conjunction with endometrial thickness measurement for detecting intrauterine pathology in asymptomatic postmenopausal women. DESIGN: Asymptomatic postmenopausal women (n = 60, mean age 52.7 +/- 4.5 years, amenorrhea > or = 6 months, follicle stimulating hormone > or = 40 mIU/mL) were evaluated with sonohysterography followed by endometrial biopsy before initiating hormone replacement therapy. RESULTS: Hyperplasia was detected in 5 of 22 (22.7%) patients with endometrial thickness of > 5 mm and in 0 of 38 (0.0%) patients with endometrial thickness of < or = 5 mm. When sonohysterography was performed, intracavitary pathology was discovered in 14 of 38 (36.8%) patients with endometrial thickness of < or = 5 mm (10 polyps, three submucosal myomas, and one septate uterus) and 14 of 22 (63.6%) patients with endometrial thickness of > 5 mm (nine polyps, four submucosal myomas, and one Asherman's syndrome). CONCLUSIONS: Endometrial thickness of < or = 5 mm excludes hyperplasia but does not eliminate other intrauterine pathology that may be discovered by sonohysterography.

Counseling the infertile couple: when enough is enough.

Therapy of infertility rarely offers a clear end point for cessation after repeated failure. Yet fertility treatment, especially if repeatedly unsuccessful, is associated with economic as well as emotional cost. Stopping treatment becomes an increasingly important option for couples whose therapy does not produce the desired result. It is the clinician's obligation to make infertile couples aware of this option early in the treatment plan and to give specific suggestions that allow these couples to stop treatment at a medically arbitrary, yet temporally well-defined point. To this end, we suggest the following for infertile couples undergoing treatment: 1) an ongoing relationship with a qualified counselor; 2) the best estimates for pregnancy rates, including the background (treatment-independent) rate, for all forms of treatment available at any point in time; 3) the option of stopping treatment from the start; 4) encouragement to seek second opinions throughout treatment; 5) time off from treatment; and 6) the opportunity to set arbitrary but relatively firm time limits. Incorporation of these suggestions into the therapeutic plan for infertile couples underscores the imperfect nature of infertility treatment and acknowledges that sometimes the most we can do for our patients is to help them stop.

In vitro fertilization in unstimulated cycles: a clinical trial using hCG for timing of follicle aspiration.

In vitro fertilization (IVF) was performed in normally ovulatory women after the follicular phase of an unstimulated cycle. Twenty patients initiated 36 cycles of unstimulated IVF, with serial ultrasound examinations and hCG 10,000 IU given when the follicle was mature. Thirty aspirations were carried out under intravenous sedation with transvaginal ultrasound guidance. One or more oocytes were obtained in 29 aspirations (97%) for a total of 52 oocytes (average 1.7); 37 fertilized (71%), two were polyspermic, and 35 cleaved (67%). Seventeen aspirations (57%) yielded multiple oocytes. All 25 oocytes obtained from dominant follicles fertilized (100%), and 12 of 27 oocytes from secondary follicles fertilized (44%) (P less than .05 versus dominant follicles), with one polyspermic fertilization in each group. Sixteen cycles resulted in a single embryo transfer (ET), eight had two embryos, and one had three embryos transferred (36% multiple ET). Five clinical pregnancies (20% per ET, 17% per retrieval) resulted in four ongoing pregnancies (16% per ET, 13% per retrieval), all singletons. Our results suggest that in selected cases, IVF in unstimulated cycles may be a clinically viable alternative to stimulated cycles, with preliminary success rates in the range of national averages for stimulated cycles.

Successful delivery after age 50: a report of two cases as a result of oocyte donation.

BACKGROUND: Because of donor oocyte programs, women who previously were considered too old to successfully achieve conception and delivery can now bear children. To our knowledge, there have been no previous reports of pregnancy outcome in women over age 50 who conceived using donor oocytes. This study presents the pregnancy and delivery data on two women who delivered at age 52. CASES: Case 1 was a 51-year-old woman, gravida 3, para 3, whose three children had been conceived with her first husband more than 20 years previously. She had remarried 18 years before presentation and had been actively trying to conceive for the last 7 years. She was diagnosed as being in menopause based on elevated gonadotropins, amenorrhea, and failure to have progesterone-withdrawal menses. She conceived on her first embryo transfer cycle with embryos derived from donor oocytes and fertilized by her husband's sperm (oocytes were donated by a woman who was undergoing retrieval for in vitro fertilization). During pregnancy she remained healthy, but had uterine prolapse at 20 weeks. She delivered a normal healthy male at 40.5 weeks; cesarean was performed because of a presumptive diagnosis of fetal distress after 3 hours of labor, when monitoring revealed fetal heart decelerations. Case 2 was also a 51-year-old woman, gravida 6, para 4, who wished to conceive with her second husband's sperm through the donor oocyte program. She had amenorrhea of 2 years' duration and elevated gonadotropins. Conception occurred after fertilization of a donor oocyte by her husband's sperm. She had an uneventful pregnancy, but labor was induced at 38 weeks' gestation given the supposed high-risk status of this age group. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. CONCLUSION: Theoretically, the risks of pregnancy complications in older patients are magnified given the aging maternal cardiovascular system, which may predispose these women to placental insufficiency. These first two cases of donor oocyte pregnancies in women over age 50 found no maternal or fetal age-related complications. We hope these reports will encourage all researchers to share their findings so that prospective patients can make better, more informed decisions as to whether they want to participate in donor oocyte programs.

Appendectomy at cesarean section: a prospective study.

Appendectomy was performed on 40 consecutive consenting patients undergoing elective cesarean section in a clinic population. The control group consisted of all other patients undergoing elective cesarean section during the period of study. The populations were similar. Clinical infection, blood loss, gastrointestinal tract recovery rates were equal in both groups. Appendectomy added 15 minutes to the operation time and extended the hospital stay by about one-half day. There were no wound infections or serious morbidity. A fifth of the appendixes removed were abnormal, including two with inflammation and one with a carcinoid tumor. Prophylactic appendectomy does not seem to add to the risk of elective cesarean section.

Urodynamic changes following hormonal replacement therapy in women with premature ovarian failure.

The mechanism by which estrogen supplementation improves the symptom of stress incontinence in postmenopausal women is unclear. Six women with proved premature ovarian failure were studied urodynamically before and after administration of oral and vaginal estrogen to study estradiol's effects on lower urinary tract function. Regardless of the mode of administration, estrogen supplementation did not produce any significant change in urethral pressure, functional length, or cystometric parameters. However, a significant increase in pressure transmission ratio (P less than .05) to the proximal and mid-urethra was noted after the administration of vaginal estrogen cream. We conclude that estrogen alone, in the absence of aging and other known precipitating factors for stress incontinence, is of minimal significance in maintaining normal urinary tract physiology.

Corpus luteum activity in tubal pregnancy.

Corpus luteum activity was monitored in 20 women undergoing nonsurgical management of ectopic pregnancy with methotrexate and citrovorum factor (N = 15) or observation (N = 5). The functional integrity of the corpus luteum was assessed by measuring progesterone and 17-hydroxyprogesterone. Trophoblastic viability was assessed by measuring the immunoreactive beta subunit of human chorionic gonadotropin. Ten of 15 methotrexate-treated patients demonstrated initial progesterone levels above 1.0 ng/mL, declining to levels below 1.0 ng/mL after treatment. Five of 15 methotrexate-treated patients and all five managed by observation alone demonstrated progesterone and 17-hydroxyprogesterone values below 1.0 ng/mL both initially and throughout the surveillance period, leading to resolution, indicating previous death of the corpus luteum. We conclude the following regarding ectopic pregnancy: 1) Corpus luteum function declines early in the biologic history of some gestations while persisting in others, and 2) corpus luteum function varies from active to inactive independent of serum levels of immunoreactive beta-human chorionic gonadotropin.

Management of unruptured ectopic gestation by linear salpingostomy: a prospective, randomized clinical trial of laparoscopy versus laparotomy.

This study was designed to compare prospectively the parameters of morbidity, cost, length of hospital stay, and fertility outcome after linear salpingostomy by laparoscopy versus laparotomy. Entry criteria included stable vital signs, hematocrit greater than 30%, age over 18 years, and desire for future fertility. All patients underwent diagnostic laparoscopy. Sixty patients with unruptured ectopic gestations of 5 cm or smaller were randomized to either laparoscopy (N = 30) or laparotomy (N = 30). Postoperative follow-up included serial measurements of serum beta-hCG titers at 3-day intervals and hysterosalpingography at 12 weeks. The laparoscopy and laparotomy groups were similar in age, height, weight, gravidity, gestational age, hematocrit, ectopic pregnancy size, and preoperative beta-hCG levels. The estimated blood loss was significantly (P less than .001) lower in patients undergoing laparoscopy, and was not affected by vasopressin injection. Two patients in the laparoscopy group required laparotomy for hemostasis, and two patients undergoing laparotomy had wound infection. One patient in each group had persistent trophoblastic activity. Baseline serum beta-hCG levels and the rate and magnitude of postoperative beta-hCG decline were similar in both groups. The length of hospital stay was significantly (P less than .001) shorter after laparoscopic salpingostomy (1.4 +/- 0.1 days) than after laparotomy (3.3 +/- 0.2 days). Postoperative hysterosalpingography showed patency of the involved tube in 16 of 20 (80%) and 17 of 19 (89%) of patients in the laparoscopy and laparotomy groups, respectively. Pregnancy rates were ten of 18 (56%) and 11 of 19 (58%) in these groups, respectively, and all pregnancies were conceived within 6 months of surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

An instrument for the recovery of preimplantation uterine ova.

This report describes an instrument to recover fertilized ova from the human uterus without anesthesia. Two hundred sixty-five lavages were performed on 20 normal and presumed fertile women and on seven infertile women. Using 60 mL of fluid, median fluid recovery was 97% (range 65-100%). In the fertile women, ova were recovered in 40 of 90 insemination cycles (44%). Complications were rare (3%), but included two retained pregnancies, three minor pelvic infections, three occurrences of catheter kinking on insertion, and one failure to obtain insertion. Reproductive function in the subjects after repeated use does not appear to be impaired.

Triplet pregnancy following oocyte donation to a functionally agonadal woman.

Reported is the first triplet gestation following oocyte donation to an agonadal woman. The transfer of five ova resulted in implantation of all five, with continued embryonic development in three. Pregnancy support was provided by exogenously administered oral E2 and intramuscular P for 100 days, at which time placental hormone production solely maintained the gestations.

Utility and predictive value of a rapid measurement of urinary pregnanediol glucuronide by enzyme immunoassay in an infertility practice.

STUDY OBJECTIVE: To assess the clinical utility of measuring urinary pregnanediol glucuronide in random samples in an infertility practice. DESIGN: Samples of urine were collected from patients approximately 3 weeks from their last menstrual period to ascertain if ovulation had occurred. Each sample was tested for specific gravity before analyzing for pregnanediol glucuronide. Simultaneous venipuncture was performed to compare results from the urinary assay to quantitative measures of serum progesterone (P). SETTING: All patients were randomly sampled. PATIENTS: Three hundred ninety women undergoing pituitary down regulation with leuprolide acetate were chosen for study because they routinely initiate medication after documentation of ovulation. OUTCOME MEASURES: The performance of the urinary pregnanediol glucuronide was evaluated as to its sensitivity, specificity, predictive value, and test efficiency compared with a serum measurement of 2.5 ng/mL and 10.0 ng/mL. RESULTS: The performance characteristics of the pregnanediol glucuronide assay were directly related to the hydration status of the patient at the time of sample collection. Regardless of urine specific gravity, if pregnanediol glucuronide was qualitatively detected (greater than 3 micrograms/mL), serum P was greater than 2.5 ng/mL. However, in cases in which pregnanediol glucuronide was undetected (less than 3 micrograms/mL), results were only accurate when the specific gravity was greater than or equal to 1.020. When comparing urinary pregnanediol glucuronide values to serum greater than 10 ng/mL, both specificity and predictive value of a positive test decreased because of increased numbers of false-positive results. CONCLUSIONS: The enzyme immunoassay measurement for pregnanediol glucuronide may replace the use of serum P in documenting the ovulatory status of many patients. However, all specimens must be checked for specific gravity and if less than 1.020, a serum P should be used to ensure accuracy.

Mishaps and misfortunes: complications that occur in oocyte donation.

Despite careful screening and the adherence to strict protocol, approximately 2% of initiated cycles of oocyte donation were found to be complicated by difficulties incurred by oocyte donors. The risk of these adverse events appeared to be limited to the initial trial of donation with experienced donors being more reliable. Thus, surveillance of the cycle's progress should be maximal during this time. Both donors and recipients need to be aware of the unique problems posed by oocyte donation to provide full informed consent. This includes the possibility for unplanned pregnancies when discontinuing the donors' usual method of contraception. These mishaps underscore the importance of reminding patients that cycle success cannot be guaranteed, and unexpected complications cannot be entirely avoided.

Embryo donation: a programmed approach.

OBJECTIVE: To describe the establishment of an embryo donation program using a large oocyte donor registry to produce embryos. DESIGN: Descriptive study. SETTING: A university-based practice. PATIENT(S): Embryos were obtained either through traditional donation from couples who underwent IVF-ET (n = 8) or through ovum donation (n = 15) with embryos produced by the program. In select cases, ovum donors were inseminated either with donor sperm selected following an advance directive from the patient or couple (n = 13) or with sperm designated by an IVF medical advisory board (n = 11). INTERVENTION(S): Donated embryos or donor oocyte/donor sperm embryos were provided to patients with backgrounds and physical attributes compatible with the embryonic phenotype. In some of the cycles, fresh ET was performed, with embryos shared among two, three, or four couples (n = 18); in other cycles, embryos were cryopreserved and transferred later (n = 21). MAIN OUTCOME MEASURE(S): Clinical and ongoing-delivered pregnancy rates. RESULT(S): The mean (+/-SD) numbers of embryos for cycles in which fresh ET and frozen ET was performed were 3.1+/-0.7 (range, 2-5) and 3.6+/-0.2 (range, 3-5), respectively. The clinical and ongoing-delivered pregnancy rates were 44.4% (8/18) and 33.3% (6/18), respectively, for cycles in which fresh ET was performed and 57.1% (12/21) and 47.6% (10/21), respectively, for cycles in which frozen ET was performed. CONCLUSION(S): Embryo donation is an alternative approach to assisted reproduction that meets the needs of single and lesbian women as well as older and less affluent couples. It is a cost-effective and efficacious means of achieving pregnancy.

Very high serum estradiol levels are not detrimental to clinical outcome of in vitro fertilization.

The use of gonadotropin-releasing hormone agonists as adjuncts to ovulation induction for in vitro fertilization (IVF) has resulted in increases in oocyte recovery rates. Along with increased oocyte number, greatly increased estradiol (E2) levels have been found. We sought to determine the clinical effect of very high E2 levels on the outcome of IVF cycles. Estradiol levels were measured in 141 patients undergoing controlled ovarian hyperstimulation with leuprolide acetate and human menopausal gonadotropin for IVF. Whereas the number of oocytes recovered and fertilized and the number of embryos available for cryopreservation were directly proportional to the E2 level, the fertilization rate and embryo cleavage rates were unrelated to the E2 level. When the patients were grouped in thirds according to E2 levels, pregnancy rate (PR) was highest in the patients with the highest E2 levels (E2 greater than 2,777 pg/mL, PR = 37%). One mild, one moderate, and one severe case of ovarian hyperstimulation syndrome occurred in patients with E2 greater than or equal to 3,000 pg/mL (n = 21), but in general, high E2 levels were attained with few complications. We conclude that high E2 levels are not detrimental to the pregnancy outcome of IVF. Our experience further suggests that cycles with E2 levels of less than or equal to 5,000 pg/mL need not be canceled and can proceed to oocyte recovery and embryo transfer.

Pregnancy after in vitro fertilization in a patient with stage I endometrial carcinoma treated with progestins.

A 35-year-old woman with chronic anovulation and bilateral tubal disease was found during infertility evaluation to have grade I endometrial carcinoma confined to an endometrial polyp. She was treated with polypectomy and endometrial curettage followed by high-dose progestagens for 6 months. Endometrial curettage at 3 and 6 months of therapy indicated regression of the lesion and the patient subsequently achieved successful pregnancy with IVF.