Low dose human chorionic gonadotropin administration at the time of gonadotropin releasing-hormone agonist trigger versus 35 h later in women at high risk of developing ovarian hyperstimulation syndrome - a prospective randomized double-blind clinical trial.

BACKGROUND: Ovarian hyperstimulation syndrome remains a serious complication during in vitro fertilization cycles if high dose human chorionic gonadotropin (hCG) is used to trigger ovulation in high responder patients. Though much of this risk is mitigated with trigger using gonadotropin releasing-hormone (GnRH) agonist alone, it may result in lower birth rates. GnRH-agonist trigger and adjuvant low dose hCG has been proposed to improve birth rates, but timing of this hCG support to corpus luteum function has never been fully described. In this randomized, prospective trial, we explore differences in live birth rates and incidence of ovarian hyperstimulation syndrome (OHSS) in high-responder patients undergoing in vitro fertilization (IVF) receiving low dose hCG at the time of GnRH-agonist (dual trigger) or hCG adjuvant at the time of oocyte retrieval. Does the timing of hCG support make a difference? RESULTS: Thirty-four subjects high-responder patients were randomized to receive low-dose hCG at the time of GnRH-agonist trigger (Group 1) and 37 received low-dose hCG at the time of oocyte retrieval (Group 2). There were no differences in the baseline characteristics and outcome of ovarian stimulation between the two groups. There were no differences in the live birth rates between Group 1 and Group 2 by intention-to-treat (14/34, 41.2% versus 21/37, 56.8%, p = 0.19) or per-protocol (14/26, 53.8% versus 19/31, 61.3%, p = 0.57) analyses. There was a slightly higher incidence of OHSS in Group 2 compared to Group 1 although the difference was not statistically significant (3/31, 9.7% versus 1/26, 3.8%). All the cases of OHSS in Group 2 were moderate while the one case of OHSS in Group 1 was mild. CONCLUSIONS: For high responder patients receiving GnRH-agonist trigger, low dose hCG supplementation allowed high pregnancy rates after fresh embryo transfer, regardless of whether it was given at the time of trigger or at oocyte retrieval. Dual trigger may be preferable to reduce the risk of OHSS.

New contraceptive methods.

As the number of abortion procedures performed each year reaches nearly 1 million, the incentive to decrease the incidence of unwanted pregnancy in the United States is high. Better education regarding women's health issues and enhanced contraceptive development are necessary to impact this long-standing problem. Several new contraceptive products are likely to become available in years to come to increase the number of choices that women and their health care providers have for pregnancy prevention. These products include long-acting implants, the levonorgestrel intrauterine device, patches, and the vaginal ring. This article surveys the near future of male and female contraception.

The role of selective oestrogen receptor modulators in the treatment of endometrial bleeding in women using long-acting progestin contraception.

This paper explores the concept that endometrial breakthrough bleeding results from the stimulatory effects of oestrogen in the endometrium. Though 'progestin-only' contraceptive regimens have long been associated with user dissatisfaction because of unpredictable vaginal bleeding, it is likely that the substantial contribution of endogenous ovarian oestradiol during such treatments predisposes the bleeding problems. Oestrogen causes endometrial proliferation, hyperplasia and neoplasia if unopposed. Oestrogen allows production of growth factors supporting angiogenesis which results in an abundance of dilated or fragile endothelial surface blood vessels, predisposing this tissue to bleeding when these vessels lose competence.

Complications of laparoscopy. Strategies for prevention and cure.

With a detailed knowledge of pelvic anatomy, familiarity with the many laparoscopic instruments, and attention to the details of good technique, many of the complications of laparoscopy described in this article can be avoided. The information presented complements that in the other articles in this issue and briefly summarizes many salient lessons already published in other excellent texts. The focus is on the most common laparoscopic complications, namely, those associated with insufflation and trocar insertion, such as vascular injury and bowel perforation. Other complications that may arise during adhesiolysis, removal of and bleeding from an ectopic pregnancy, and specimen removal from the abdomen are also discussed.

Chronic antiprogestin therapy produces a stable atrophic endometrium with decreased fibroblast growth factor: a 1-year primate study on contraception and amenorrhea.

OBJECTIVE: To describe the efficacy of mifepristone in the prevention of menstrual bleeding and ovulation, with similar observations in comparison groups. DESIGN: Prospective experimental study. Thirty-two cynomolgus monkeys were divided equally into four treatment groups (n = 8). Treatment lasted for 1 year. INTERVENTION(S): Group I received GnRH-agonist (GnRH-a) and in-sequence mifepristone, group II received mifepristone only, group III received GnRH-a only, and group IV received vehicle control. MAIN OUTCOME MEASURE(S): Serum estradiol and progesterone, menstrual bleeding, endometrial thickness, and endometrial expression of basic fibroblast growth factor (bFGF) as determined by immunohistochemistry. RESULT(S): Weekly progesterone determinations showed that mifepristone-treated monkeys seldom ovulated (6 ovulations in 8 years), compared with the controls (100 ovulations in 8 years), while maintaining early to midfollicular levels of circulating serum estradiol. The GnRH-a-only group also rarely ovulated, but was chronically and severely hypoestrogenic. The mifepristone-only group showed scant menstrual bleeding (5 days in 8 years) as compared with the menstrual frequency in control animals (422 days in 8 years). Endometrial proliferation, as determined by biopsy, was similarly minimal for both the GnRH-a and mifepristone groups, and statistically less than in control monkeys. Both the mifepristone and GnRH-a treatments suppressed endometrial gland expression of the angiogenesis polypeptide bFGF. CONCLUSION(S): Chronic mifepristone induced anovulation along with virtual amenorrhea, which suggests the worth of this novel hormonal contraceptive.

Pelvic adhesions contain sex steroid receptors and produce angiogenesis growth factors.

OBJECTIVE: To evaluate female pelvic adhesion tissue for the presence of estrogen receptor (ER), progesterone receptor (PR), basic fibroblastic growth factor (basic-FGF), and vascular endothelial growth factor (VEGF). DESIGN: Descriptive study. SETTING: Patients at a tertiary medical center. PATIENTS: Female reproductive age patients undergoing gynecologic surgery who were not receiving hormonal therapy. INTERVENTIONS: Female reproductive tract peritoneal adhesion tissue was excised, frozen, and sent for immunohistologic evaluation. MAIN OUTCOME MEASURE: Presence of ER, PR, basic-FGF, and VEGF in adhesion tissue. RESULTS: Nineteen of 19 specimens were positive for PR; 16 of 19 specimens were positive for ER, which was present in a variety of the different cell types constituting adhesion. Vascular endothelial growth factor and basic-FGF were detected in endothelial cells of blood vessels supplying this tissue as well as in mesothelial cells. CONCLUSION: Adhesion tissue contains ER, PR, and growth factors that may be important in the genesis of the permanent fibrovascular bands between pelvic organs. This supports the theoretical possibility of hormonal manipulation of these tissues to negatively influence postoperative pelvic adhesion formation.

Role of hypoestrogenism or sex steroid antagonism in adhesion formation after myometrial surgery in primates.

OBJECTIVE: To determine the contribution of estrogen in the development of pelvic adhesions during myometrial surgery. DESIGN: A randomized, prospective study in the nonhuman primate. SETTING: A primate colony, Department of Obstetrics and Gynecology, Eastern Virginia Medical School. INTERVENTIONS: All primates were assigned prospectively to one of three treatment groups: [1] GnRH analogue (GnRH-a), [2] mifepristone, or [3] vehicle control. After 3 months of treatment, a standard uterine fundal hysterotomy, for full thickness endometrial biopsy, was performed at the time of exploratory laparotomy, with subsequent scoring of utero-omental adhesions to the hysterotomy site at a future staging procedure based upon adhesion area, vascularity, and tenacity. Serum was drawn on the day of surgery for E2 determination. Endometrial height, from the surface interface between the endometrium and myometrium, was used as a bioassay of estrogen activity. RESULTS: The hypoestrogenic (GnRH-a) group and the mifepristone group had significantly fewer utero-omental adhesions compared with the normally cycling control monkeys as measured by a lower adhesion score. Similarly, the endometrial thickness was significantly reduced in the GnRH-a and mifepristone groups (one-third) compared with the cycling controls, demonstrating the effects of either hypoestrogenism or noncompetitive estrogen antagonism. Serum E2 on the day of surgery was predictive of the postoperative adhesion score by both a regression analysis and analysis of covariance. CONCLUSIONS: The actions of E2 seem to have a dramatic effect on the formation of pelvic adhesions after myometrial surgery.

Antiprogestin and/or gonadotropin-releasing hormone agonist for endometriosis treatment and bone maintenance: a 1-year primate study.

The fact that RU 486 curtailed estrogen-induced endometrial proliferation in primates and relieved pelvic pain in women with endometriosis is the reason for continuing research on antiprogestins. Thirty-two adult female cynomolgus monkeys demonstrating menstrual regularity had surgery for the induction of endometriosis. After lesion staging, four treatment groups (n = 8), each of 1-yr duration, were made. Group I received combination/sequential therapy with depot GnRH agonist (GnRH-a) for 3 months, followed by weekly RU 486 for 9 months. Group II received weekly RU 486, group III received monthly GnRH-a, and group IV served as a vehicle control. A staging laparotomy was performed every 3 months to assess the area of peritoneal endometriosis (square centimeters) and the thickness of in situ endometrium. Bone density was measured serially by dual x-ray absorptiometry. Serum was collection weekly. Mean (+/- SE) serum estradiol levels were lower after GnRH-a (77.1 +/- 2.6 pmol/L) than after RU 486 (231 +/- 12 pmol/L) treatment and lower than those in untreated cycling controls (231 +/- 13 pmol/L). GnRH-a produced significant atrophy of endometriotic plaques within 3 months of therapy; this lesion reduction was sustained with RU 486. Both GnRH-a and RU 486 alone produced profound thinning of ectopic and eutopic endometrium throughout 1 yr of continuous therapy. Bone density decreased significantly after 6 months of GnRH-a alone (P < 0.05), without significant changes in the other groups. After RU 486 treatment, there were no significant changes in testosterone, androstenedione, sex hormone-binding globulin, or cortisol. Like GnRH-a, long term antiprogestin therapy produced a reduction in the volume of pelvic endometriotic lesions as well as atrophy of in situ endometrium; however, RU 486 allowed maintenance of tonic ovarian estradiol secretion, suggesting that efficacious endometriosis therapy can be sustained long term without the sequelae of hypoestrogenism, specifically bone density loss.

Increase in androgen:estrogen ratio specifically during low-dose follicle-stimulating hormone therapy for polycystic ovary syndrome.

OBJECTIVES: To compare changes in serum androgens in women with polycystic ovary syndrome (PCOS) during ovulation induction with low-dose versus conventional urofollitropin. DESIGN: Prospective case-control study. SETTING: Tertiary-care reproductive medicine center. SUBJECTS: Thirty-three women with PCOS who failed to conceive with clomiphene citrate therapy. INTERVENTIONS: Urofollitropin (low-dose, 75 IU; conventional dose, 150 IU) was administered IM daily. Therapy was monitored by serum E2 and vaginal sonography. Hormone determinations were performed by immunoassay. MAIN OUTCOME MEASURES: Serum E2, androstenedione (A), T, and LH levels. RESULTS: On the day of hCG administration, patients treated with low-dose therapy exhibited significantly higher ratios of A to E2 (3.5 +/- 0.5 versus 2.2 +/- 0.3 [mean +/- SEM]) and T to E2 (1.5 +/- 0.3 versus 1.0 +/- 0.1) compared with conventional urofollitropin therapy. The number of follicles > or = 16 mm in diameter was significantly lower with low-dose therapy (2.7 +/- 0.6 versus 5.4 +/- 0.4). CONCLUSIONS: Although low-dose therapy was associated with a reduction in the number of recruited follicles, the increase in androgen to E2 associated with this therapy may adversely affect oocyte quality and may explain the relatively high miscarriage rate reported in PCOS patients with this therapy.

Value of sperm morphology assessed by strict criteria for prediction of the outcome of artificial (intrauterine) insemination.

The purpose of this study was to investigate the relationship between sperm parameters and the outcome of artificial (intrauterine) insemination (IUI). One hundred and twenty-six patients undergoing 395 consecutive IUI cycles in a 1-year period in our institution were studied. In all cases, controlled ovarian stimulation and hCG-timed IUI were performed, followed by progesterone supplementation of the luteal phase. In 86 patients, (243 cycles) the husband's sperm was utilized, whereas in 40 couples (152 cycles), donor sperm was used due to severe male factor infertility. Among the sperm parameters of the original ejaculate, % normal morphology (assessed by strict criteria) was the most significant predictor of pregnancy (stepwise regression analysis, P = 0.003). Using logistic regression, morphology was the best predictor of pregnancy (r = 0.12); linearity of movement significantly enhanced the predictive value of morphology alone (r = 0.17, P = 0.004). Overall, the pregnancy rates were significantly higher (P = 0.01) in cases with > or = 14% normal morphology (15% per cycle) compared to cases with < 14% normal morphology (7% per cycle). This threshold level for morphology is in agreement with previously published IVF results. These results underscore the significance of sperm morphology assessed by strict criteria as a predictor of pregnancy outcome in the IUI setting.

Sperm morphology as diagnosed by strict criteria: probing the impact of teratozoospermia on fertilization rate and pregnancy outcome in a large in vitro fertilization population.

OBJECTIVE: To investigate the predictive value of sperm morphology assessed by strict criteria on IVF outcome. DESIGN: Retrospective analysis of all IVF cycles (January 1987 to December 1992). MAIN OUTCOME MEASURES: All patients were assigned to one of three groups based on sperm morphology: P-pattern (< 4% normal forms), G-pattern (4% to 14% normal forms), and N-pattern (> 14% normal forms). Morphology pattern was related to other semen characteristics and IVF outcome. RESULTS: Despite corrective measures at oocyte insemination, the fertilization rate was significantly different among the three morphology groups, P < G < N. N-pattern sperm produced a mean fertilization rate over 85% regardless of low motility or concentration. In a cohort study, P-pattern cycles produced a lower implantation rate and lower ongoing pregnancy rate, independent of the lower fertilization rate. CONCLUSIONS: Strict morphology is an excellent biomarker of sperm fertilizing capacity, independent of motility and concentration. P-pattern sperm may denote a poorer prognosis for establishing a pregnancy, even after a satisfactory fertilization rate is achieved.

The reduction of postoperative adhesions by two different barrier methods versus control in cynomolgus monkeys: a prospective, randomized, crossover study.

OBJECTIVES: To determine the effectiveness of two different surgical membranes in preventing postoperative adhesions as compared with control and to evaluate the benefit as compared with "second-look" adhesiolysis. DESIGN: A randomized, prospective, crossover study. SETTING: A colony of individually caged non-human primates, Department of Obstetrics and Gynecology, Eastern Virginia Medical School Norfolk, Virginia. INTERVENTIONS: Hysterotomy or adhesiolysis at the time of exploratory laparotomy, with subsequent scoring of adhesions based on area, vascularity, tenacity, and adhesion score. RESULTS: The combined crossover data reveal that both surgical barriers are superior in adhesion prevention to microsurgical technique alone. Expanded polytetrafluoroethylene (Gore-Tex Surgical Membrane; WL Gore and Associates, Flagstaff, AZ) was better than oxidized regenerated cellulose (Interceed; Johnson and Johnson Medical, Inc., Arlington, TX) with respect to adhesion area, tenacity, and vascularity, with a significant improvement in the total adhesion score. Second-look adhesiolysis resulted in significant adhesion reduction in the control group, making second-look adhesiolysis statistically similar to the use of either barrier alone (without subsequent adhesiolysis). Gore-Tex removal does not result in adhesion formation as determined by third-look surgery. CONCLUSIONS: Both Interceed and Gore-Tex show a reduction in the prevention of postsurgical adhesions after hysterotomy incisions, as compared with microsurgical technique alone. Second-look adhesiolysis is as effective as either barrier in the reduction of permanent pelvic adhesions.

Transcervical tubal cannulation: a review.

Rapid progress has been made in the last 10 years regarding minimally invasive access to the human fallopian tube. Coaxial catheter systems are being used with hysteroscopy, fluoroscopy, ultrasonography, and tactile sensation to cannulate the fallopian tube transcervically with consistent success. Uterotubal obstruction viewed at the time of hysterosalpingogram can often be successfully cannulated with intrauterine pregnancies resulting. This review surveys all available published series of transcervical tubal cannulation with discussion of methodology, success in establishing patency, and the resultant pregnancy rates. It also describes how this technology has been applied to the intratubal deposition of gametes and embryos, direct visualization of the tubal epithelium, (falloposcopy), and contraception. Collectively, these techniques are defining tubal pathology more precisely, allowing us to prescribe the proper therapy.

Proximal tubal occlusion by hysterosalpingogram: a role for falloposcopy.

Eight infertility patients with proximal tubal occlusion by HSG and at least one other independent method underwent falloposcopy to evaluate the etiology of uterotubal occlusion. Patency was established in 9 of 12 tubes evaluated. Falloposcopy revealed 5 tubes with multiple or extensive intratubal lesions that would be unsuitable for unilocular tubal resection with subsequent reanastomosis. In addition, 5 tubes were visually normal or had only minor pathological changes (2 of these patients became pregnant). Only 2 of the tubes examined in a single patient would be considered candidates for microsurgical correction at laparotomy. Falloposcopy will become a useful adjunct in the evaluation of the patient with suspected tubal infertility. It provides information regarding the condition of the tubal mucosa that is unavailable by any other technique, adding precision to surgical techniques when they are deemed necessary while directing other patients to assisted reproductive technologies. However, falloposcopy is still in its infancy and data from larger studies are needed.

Effect of measurement variability on Rossavik growth model specification and prediction of growth outcome at birth.

We have studied how variability in second-trimester ultrasound measurements affects the process of fetal growth evaluation based on individual fetal growth curve standards specified by Rossavik growth models. The head and abdominal short axes of two second-trimester scans of a patient with normal fetal growth were increased or decreased by increments ranging from 0.1 cm to values equal to the two standard deviations of the interobserver variability for these measurements--i.e., 0.3 cm for head short axis and 0.4 cm for abdominal short axis. The largest increments affected the Growth Potential Realization Index for weight at birth by 1% to 13% when applied to head short axis, and by 2% when applied to abdominal short axis. In contrast, the same increments had little effect (1%) on the Growth Potential Realization Indices for head and abdominal circumferences. Whereas 0.1-cm increments had no effect on any of the individual growth models or predicted birth characteristics, some combinations of these small errors involving both head and abdominal short axes changed the Growth Potential Realization Index for weight by as much as 15%, and those for head and abdominal circumferences by 3% and 8%, respectively. Under some scenarios, fetal growth status could be falsely classified as normal or abnormal. These results show that the reliability of individualized growth assessment depends to a great extent on excellent ultrasound technique, at least for certain parameters.

Treatment of adenomyosis with long-term GnRH analogues: a case report.

Presented here is the first reported case of biopsy-proved adenomyosis treated medically with long-term GnRH analogue. Uterine volume, as calculated by serial ultrasound measurements, was reduced by 65% after 4 months and remained small several months after discontinuation of therapy. Size reduction was accompanied by amenorrhea and relief of severe dysmenorrhea. Though not proposed as a substitute for surgery, GnRH analogue may be useful as a surgical adjuvant or for temporary reduction of symptoms.

Detection of macrosomia by the individual fetal growth curve assessment method.

The value of the Rossavik growth model [P = c(t)k + s(t)] was evaluated in 39 patients with singleton pregnancy who had neonatal weight outcome above the 90th percentile of our birth weight distribution for gestational age. Individual fetal growth curve standards for head and abdominal circumferences, femur diaphysis length, and weight were determined from the data of two scans obtained before 26.1 weeks' gestation and separated by an interval of at least 5 weeks. Projected crown-heel lengths were calculated from projected femur diaphysis length values. Comparisons between actual and predicted birth characteristics were expressed by the Growth Potential Realization Index (GPRI) and Neonatal Growth Assessment Score (NGAS). Excessive growth at birth was seen in almost all cases as indicated by high GPRI for weight and abdominal circumference and abnormal NGAS values. In eight of the 33 patients who delivered after 38 weeks, excessive growth was detected only by comparing birth characteristics to their predicted values at 38 weeks' gestation. Our data suggest that individual growth curve standards may identify several patterns of excessive fetal growth that could represent different pathophysiologic mechanisms, ie, failure to terminate growth after 38 weeks versus a defect in a still unknown growth regulator. The individual fetal growth curve standards method gives additional information and discriminates well between normal and excessive fetal growth.

Twin pregnancy after orthotopic liver transplantation, with exacerbation of chronic graft rejection.

We report the sixth pregnancy and the first occurrence of twins after liver transplantation, and the second time cyclosporine was used in pregnancy for that indication. The pregnancy was interrupted at 33 weeks, menstrual age, for exacerbation of chronic graft rejection and intrauterine growth retardation of both twins with possible fetal compromise. The neonatal outcomes were good without any detected anomalies except for some neurodevelopmental problems in one twin at the long-term follow-up. The mother underwent a second liver transplant shortly after delivery.