Ovarian hyperstimulation syndrome: review and new classification criteria for reporting in clinical trials.

STUDY QUESTION: What is an objective approach that employs measurable and reproducible physiologic changes as the basis for the classification of ovarian hyperstimulation syndrome (OHSS) in order to facilitate more accurate reporting of incidence rates within and across clinical trials? SUMMARY ANSWER: The OHSS flow diagram is an objective approach that will facilitate consistent capture, classification and reporting of OHSS within and across clinical trials. WHAT IS KNOWN ALREADY: OHSS is a potentially life-threatening iatrogenic complication of the early luteal phase and/or early pregnancy after ovulation induction (OI) or ovarian stimulation (OS). The clinical picture of OHSS (the constellation of symptoms associated with each stage of the disease) is highly variable, hampering its appropriate classification in clinical trials. Although some degree of ovarian hyperstimulation is normal after stimulation, the point at which symptoms transition from those anticipated to those of a disease state is nebulous. STUDY DESIGN, SIZE, DURATION: An OHSS working group, comprised of subject matter experts and clinical researchers who have significantly contributed to the field of fertility, was convened in April and November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: The OHSS working group was tasked with reaching a consensus on the definition and the classification of OHSS for reporting in clinical trials. The group engaged in targeted discussion regarding the scientific background of OHSS, the criteria proposed for the definition and the rationale for universal adoption. An agreement was reached after discussion with all members. MAIN RESULTS AND THE ROLE OF CHANCE: One of the following conditions must be met prior to making the diagnosis of OHSS in the context of a clinical trial: (i) the subject has undergone OS (either controlled OS or OI) AND has received a trigger shot for final oocyte maturation (e.g. hCG, GnRH agonist [GnRHa] or kisspeptin) followed by either fresh transfer or segmentation (cryopreservation of embryos) or (ii) the subject has undergone OS or OI AND has a positive pregnancy test. All study patients who develop symptoms of OHSS should undergo a thorough examination. An OHSS flow diagram was designed to be implemented for all subjects with pelvic or abdominal complaints, such as lower abdominal discomfort or distention, nausea, vomiting and diarrhea, and/or for subjects suspected of having OHSS. The diagnosis of OHSS should be based on the flow diagram. LIMITATIONS, REASONS FOR CAUTION: This classification system is primarily intended to address the needs of the clinical investigator undertaking clinical trials in the field of OS and may not be applicable for the use in clinical practice or with OHSS occurring under natural circumstances. WIDER IMPLICATIONS OF THE FINDINGS: The proposed OHSS classification system will enable an accurate estimate of the incidence and severity of OHSS within and across clinical trials performed in women with infertility. STUDY FUNDING/COMPETING INTERESTS: Financial support for the advisory group meetings was provided by Merck & Co., Inc., Kenilworth, NJ, USA. P.H. reports unrestricted research grants from MSD, Merck and Ferring, and honoraria for lectures from MSD, Merck and IBSA. S.M.N. reports that he has received fees and grant support from the following companies (in alphabetic order): Beckman Coulter, Besins, EMD Serono, Ferring Pharmaceuticals, Finox, MSD and Roche Diagnostics over the previous 5 years. P.D., C.C.C., J.L.F., H.M.F., and P.L. report no relationships that present a potential conflict of interest. B.C.T. REPORTS: grants and honorarium from Merck Serono; unrestricted research grants, travel grants and honorarium, and participation in a company-sponsored speaker's bureau from Merck Sharp & Dohme; grants, travel grants, honoraria and advisory board membership from IBSA; travel grants from Ferring; and advisory board membership from Ovascience. L.B.S. reports current employment with Merck & Co, Inc., Kenilworth, NJ, USA, and owns stock in the company. K.G. and B.J.S. report prior employment with Merck & Co., Inc., Kenilworth, NJ, USA, and own stock in the company. All reported that competing interests are outside the submitted work. No other relationships or activities exist that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: Not applicable.

Macrophage secretory products and sperm zona pellucida binding.

OBJECTIVE: To determine if exposure of human gametes to macrophage secretory products reduces sperm binding to the zona pellucida, and to determine which cytokine(s) may be responsible for this effect. METHODS: A human macrophage cell line was cultured and either activated with lipopolysaccharide for 2 hours and then washed or left unactivated. Culture-conditioned media from activated or unactivated cells was used in hemizona assay. Hemizonae were incubated with sperm suspended in culture medium from either unactivated macrophages or activated macrophages, with the matching hemizona incubated with sperm suspended in control medium. Matching hemizonae were incubated with sperm suspended in unactivated macrophage medium paired with sperm suspended in activated macrophage culture medium. Conditioned medium from activated macrophages was found to have elevated levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta, and transforming growth factor-beta, therefore, gametes were also exposed to these cytokines followed by the hemizona assay. After each incubation, the number of sperm tightly bound to the outer surface of each hemizona was determined. RESULTS: Exposure of gametes to activated and unactivated macrophage culture-conditioned media significantly decreases sperm binding to the zona pellucida, with medium from activated macrophages inducing the greatest effect (P < .05). Exposure of sperm to TNF-alpha significantly impaired sperm binding (P < .05), whereas other cytokines tested had no effect. CONCLUSION: These results suggest that macrophage secretory products in the basal and activated state may be a factor in endometriosis-associated infertility through the interference of sperm binding to the zona pellucida, and that TNF-alpha is a key cytokine responsible for this effect.

Microsurgical tubal anastomoses performed as an outpatient procedure by minilaparotomy are less expensive and as safe as those performed as an inpatient procedure.

OBJECTIVE: To determine the cost-effectiveness, safety, and success of microsurgical tubal anastomoses performed by minilaparotomy as an outpatient. DESIGN: Retrospective. SETTING: Military tertiary care medical center. PATIENT(S): Seventy consecutively seen women of reproductive age who were undergoing surgical reversal of sterilization from August 1, 1993, through August 1, 1995. INTERVENTION(S): Microsurgical sterilization reversal by minilaparotomy was performed as an inpatient (group 1, 47 patients) or as an outpatient (group 2, 23 patients). MAIN OUTCOME MEASURE(S): Cost, complication rate, pregnancy rate. RESULT(S): The procedure cost more for inpatients ($3,116) than for outpatients (!,456). Pregnancy rates were similar (56% in group 1 vs. 75% in group 2). There was only one complication in the series. CONCLUSION(S): Outpatient microsurgical sterilization reversal performed by minilaparotomy is as safe and effective as the inpatient procedure and is less expensive.

PIP: A retrospective study conducted at a military tertiary care medical center in Portsmouth, Virginia (US), assessed the cost-effectiveness, safety, and success of microsurgical tubal anastomoses performed by minilaparotomy on an outpatient basis. The medical records of 70 consecutive women who underwent surgical sterilization reversal at the facility in 1993-95 were reviewed; 47 women received minilaparotomy as an inpatient procedure and 23 on an outpatient basis. All patients were seen in the clinic 2-4 weeks postoperatively and no significant complications were recorded. The total cost of the procedure was $3116 for inpatients and $1456 for outpatients. At follow-up (range, 19-43 months after surgery), the crude pregnancy rate was 56% in the inpatient group and 75% among women who underwent the procedure as outpatients. These findings indicate that minilaparotomy can be performed on an outpatient basis with significant cost savings but no adverse effect on patient safety. Appropriate preoperative counseling and postoperative follow-up are essential, however.

Microlaparoscopy: a comparative study of diagnostic accuracy.

OBJECTIVE: To investigate the diagnostic accuracy of microlaparoscopy in comparison to laparoscopy with a standard 10-mm laparoscope. DESIGN: Prospective evaluation by two independent observers. SETTING: Academic Medical Center. PATIENT(S): Ten patients scheduled to undergo diagnostic laparoscopy for the indications of infertility and/or chronic pelvic pain. INTERVENTION(S): Two surgeons were present for each operation. Diagnostic laparoscopy was performed using the Microlap 2-mm laparoscope (Imagyn Medical Inc., Lagun Niguel, CA). Standard diagnostic laparoscopy was then performed using a 10-mm laparoscope. After each procedure, each surgeon reported his or her observations in a confidential manner to a third person to record. MAIN OUTCOME MEASURE(S): Endometriosis and adnexal adhesions were staged. Observations made with the microlaparoscope were compared with those obtained with a standard 10-mm laparoscope for each surgeon. The observations of both surgeons were also compared with each other's to evaluate interobserver differences. RESULT(S): Operative findings reported by each individual surgeon using the microlaparoscope correlated with the operative findings reported using the larger laparoscope. Scores for both endometriosis and adnexal adhesions did not differ in any significant way. Endometriosis scores differed by no more than 6 points, and adhesion scores differed by no more than 2 points, with no subsequent change in severity classification for either finding. Furthermore, when comparing the additional operative findings of the two surgeons, no difference was noted when using either the microlaparoscope or a standard 10-mm laparoscope. CONCLUSION(S): The diagnostic accuracy achieved with microlaparoscopy is comparable to that achieved with standard 10-mm laparoscopy.

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.

Factors affecting fertilization: endometrial placental protein 14 reduces the capacity of human spermatozoa to bind to the human zona pellucida.

OBJECTIVE: To examine whether placental protein 14 (PP14) may affect directly those sperm functions crucial to fertilization and early embryo development. DESIGN: In these prospective studies, we evaluated semen samples of fertile men incubated under capacitating conditions with and without PP14. SETTING: Academic tertiary institution. INTERVENTIONS: Biologically active PP14 was purified from human midtrimester amniotic fluid by anion exchange and immunoaffinity chromatography. After separation of the motile fraction, spermatozoa were incubated for 30 minutes with or without PP14 (concentration range of 0.01 to 100 micrograms/mL), washed, and then aliquots were prepared for use in the different assays. Human sperm-zona pellucida (ZP) binding was assessed using the hemizona assay (HZA) in a 4-hour gametes coincubation period. Sperm motility parameters were evaluated using a computerized semen analyzer. The acrosome reaction (AR) was determined by fluorescein isothiocyanate-conjugated Pisum sativum agglutinin and indirect immunofluorescence. MAIN OUTCOME MEASURES: Sperm-ZP binding, sperm motility patterns, and AR. RESULTS: Preincubation of sperm (and not the hemizonae) with PP14 produced a significant and dose-dependent inhibition of binding in the HZA. Monoclonal antibodies generated against PP14 showed no direct effect in the HZA and partially neutralized the inhibitory activity of PP14 in the HZA. Insulin-like growth factor binding protein-1 (IGFBP-1), an endometrial stromal cell product, showed no effect in the HZA. Neither PP14 nor IGFBP-1 interfered with sperm motility parameters or the AR. CONCLUSIONS: Placental protein 14 produced a potent, fast, and dose-dependent inhibition of binding of human spermatozoa to the human ZP without affecting other prefertilization events (i.e., hyperactivated motility or AR). The detrimental effect on sperm-zona interaction seems to be specific for this endometrial epithelial protein (not observed with an endometrial stromal product) and may have fundamental bearance to the fertilization process thus providing a mechanism for endometriosis-related infertility.

Changes in T-cell regulation of responses to self antigens in women with pelvic endometriosis.

OBJECTIVE: To study autoimmune aspects of endometriosis. DESIGN: Lymphoblast transformation and hemolytic plaque formation were used to assess specific T- and B-cell activity against endometrial antigens. SETTING: Military teaching hospital. PATIENTS: Ninety-four healthy women of reproductive age undergoing diagnostic laparoscopy as part of an evaluation for infertility or chronic pelvalgia were accordingly grouped into those with normal pelvic peritoneum (20), mild endometriosis (50), and severe endometriosis (24). MAIN OUTCOME MEASURE: The study assessed the proliferative and humoral responses of lymphocytes from women with and without endometriosis to endometrial antigens and quantified the number of B-cell precursors, T-helper cells, and T-suppressor cells to these antigens. RESULTS: Unfractionated endometrial antigens were similarly blastogenic for lymphocytes from women with and without endometriosis. Despite equivalent numbers of B-cell precursors to these antigens, antiendometrial antibody responsiveness appears to have increased in women with mild endometriosis because of a decrease in T-suppressor cell activity and declined in women with severe endometriosis because of a further drop in T-suppressor cell activity and an increase in T-helper cell activity, as compared with women without endometriosis. CONCLUSIONS: Taken together, these experiments support the possibility that pelvic endometriosis may result from a break in specific T-cell tolerance rather than nonspecific polyclonal activation of responder lymphocytes.

Adverse effects of methylene blue on human sperm motility, components of human reproductive tract fluids, and mouse embryo cleavage.

Because methylene blue exhibits germicidal, oxidation, and reduction properties, the authors asked whether this agent causes adverse effects on gametes, embryos, and/or secretions of the reproductive tract. Time- and dose-dependent inhibition of human sperm motility by methylene blue was observed, as was growth inhibition of 2-cell mouse embryos. Furthermore, the presence of methylene blue in uterine, fallopian tube, and peritoneal fluids altered protein mobility in polyacrylamide gels, and yielded apparent values of follicle-stimulating hormone and estradiol up to 260% of actual values (P less than 0.05). These data suggest that the presence of methylene blue in reproductive tract fluids may provide a false impression of their biochemical and biophysical compositions, and that the use of methylene blue as a chromopertubation agent be conducted with appropriate awareness.

Peritoneal fluid from patients with endometriosis decreases sperm binding to the zona pellucida in the hemizona assay: a preliminary report.

OBJECTIVE: To evaluate the effect of peritoneal fluid (PF) from patients with endometriosis on gamete interaction under hemizona assay (HZA) conditions. DESIGN: The HZA was used to study the effect of PF from patients with endometriosis on sperm binding to the zona pellucida using media and normal PF as controls. SETTING: The patients were collected from a university hospital infertility clinic. PATIENTS: Peritoneal fluid from 16 women being evaluated for infertility or sterilization who were found to have endometriosis at surgery was used. Three normal patients, who were being sterilized, had PF that was used as a control. RESULTS: Results suggest that there is a significant reduction in the number of tightly bound sperm to the zona surface in endometriosis specimens as reflected in the hemizona index and that this effect is directly related to the stage of the disease. CONCLUSIONS: Although the sample is small, this methodology may help to elucidate one of the mechanisms responsible for endometriosis-associated infertility.

Pregnancy-associated protein-A does not improve predictability of pregnancy success or failure over human chorionic gonadotropin levels in early normal and abnormal pregnancy.

In the present study we sought to compare levels of PAPP-A and hCG produced by different types of pregnancy: normal, ectopic, threatened abortion and molar pregnancy after evacuation. The gestations ranged from 13 to 122 days. Serum levels of both PAPP-A and hCG were measured and compared. Chi squares analysis were predictive only for increasing trends in hCG as well as decreasing trends of both hCG and PAPP-A. Analysis of variance and linear discriminant function used to evaluate results suggested that PAPP-A did not improve predictability of hCG. The values of PAPP-A levels for the postevacuation molar pregnancies barely exceeded the lower limit of detection; thus, no meaningful comparisons could be made.

Hysteroscopic cannulation and lavage in the treatment of proximal tubal occlusion.

In two patients with apparent PTO, as diagnosed by HSG and laparoscopy, tubal patency was restored by hysteroscopic cannulation of the tubal ostia, followed by direct lavage. Tubal resection and reanastomosis/reimplantation may not be necessary for all patients with apparent PTO.

Ectopic growth of endometrium depends on its structural integrity and proteolytic activity in the cynomolgus monkey (Macaca fascicularis) model of endometriosis.

OBJECTIVE: To identify factors influencing the development of endometrial autografts in a monkey model of endometriosis. DESIGN: Prospective, comparative study. SETTING: Animal research unit. SUBJECTS: Thirty regularly cycling cynomolgus monkeys in three groups of 10 each. INTERVENTIONS: Endometrium was minced and spilled into the cul-de-sac in group 1. In group 2, the tissue additionally was digested enzymatically. In group 3, the tissue was incubated with a protease inhibitor. MAIN OUTCOME MEASURES: Staging laparotomies after 3 weeks and 3 months. RESULTS: In groups 1, 2, and 3, moderate or severe disease was seen in eight, two, and four monkeys, respectively, after 3 weeks and in eight, three, and two monkeys, respectively, at 3 months. CONCLUSIONS: An intact structure leads to ectopic implantation of endometrial fragments in most cases. Conversely, enzymatic digestion of endometrial fragments and treatment with proteinase inhibitor impair ectopic growth. Intrinsic endometrial factors that influence extracellular matrix remodeling may play a role in the pathogenesis of human endometriosis.

Evaluation of outpatient hysteroscopy, saline infusion hysterosonography, and hysterosalpingography in infertile women: a prospective, randomized study.

OBJECTIVE: To compare the diagnostic accuracy, pain scores, and procedure length of outpatient hysteroscopy (OHS), hysterosalpingography (HSG), and saline infusion hysterosonography (SIS) for evaluation of the uterine cavity of infertile women. DESIGN: Prospective, randomized, investigator-blind study. SETTING: Tertiary infertility clinic. PATIENT(S): Forty-six consecutive infertile women. INTERVENTION(S): Outpatient HSG, OHS, and SIS, followed by operative hysteroscopy (HS). MAIN OUTCOME MEASURE(S): Uterine abnormalities, procedure length, and subjective pain. RESULT(S): Fifty-nine percent of infertile subjects were found to have an abnormality on at least one of three outpatient uterine evaluations. When compared with the case of definitive operative HS, 60% of abnormalities were correctly classified by HSG, 72% by OHS, and 52% by SIS (P: NS). When comparing all combinations of 2 outpatient screening tests to operative hysteroscopy, 68% were correctly classified by HSG/OHS, 58% by HSG/SIS, and 64% by OHS/SIS (P: NS). The average time length for the OHS was 9.1 min., which was significantly greater than for both HSG (average, 5.3 min) and SIS (average, 6.1 min.) (P<.0001 for both). HSG and SIS were not statistically different regarding procedure time length. The average pain score (0-10) for SIS was 2.7, compared with 5.8 and 5.3 for HSG and OHS, respectively. Both HSG and OHS mean pain scores were significantly greater than the SIS mean. CONCLUSION(S): OHS, SIS, and HSG were statistically equivalent regarding evaluation of uterine cavity pathology in infertile women.

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.

Hemizona assay and teratozoospermia: increasing sperm insemination concentrations to enhance zona pellucida binding.

This study aimed: (1) to evaluate the zona-binding capacity of patients with abnormal sperm morphology, using standard hemizona assay (HZA) conditions and increasing sperm insemination concentration during the assay and (2) to determine the insemination concentration needed to obtain equality in the number of tightly bound sperm to matching hemizonae, using sperm from teratozoospermic patients versus proven fertile controls. The minimum concentration of motile sperm from fertile controls necessary to validate HZA results was 250,000/mL (35.4 +/- 5.6 tightly bound sperm; mean +/- SE). The "effective number of sperm" (morphologically normal with high motility) was 60,750/mL. Each teratozoospermic patient had a unique, (higher) sperm insemination concentration (range: 0.5 X 10(6) to 2.0 X 10(6) motile sperm/mL) necessary to equal the number of tightly bound sperm representing the lower 95% confidence interval for the control sample (at 0.5 X 10(6) motile sperm/mL) with the matching hemizona. These results suggest that the HZA may be used as an indicator of the sperm insemination concentration during in vitro fertilization in patients with teratozoospermia.

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.

Defining the valid hemizona assay: accounting for binding variability within zonae pellucidae and within semen samples from fertile males.

OBJECTIVE: To achieve a better understanding of the variability in sperm and oocyte binding capacities will optimize use of the hemizona assay (HZA) as a predictor of sperm function. DESIGN: Limitations of the HZA were more clearly delineated by current studies: (1) variability of sperm binding capacity of men over a 90-day interval; (2) variability of sperm binding using different oocytes; and (3) lower limits of the number of sperm bound from the fertile control in two laboratories. PATIENTS: Semen was obtained from proven fertile men and one subfertile individual. MAIN OUTCOME MEASURE: The number of sperm tightly bound to the hemizona were measured and compared. RESULTS: In the initial study, 6 fertile control men exhibited a similar degree of variability in zona binding when studied over a 90-day interval. Average sperm binding for individuals ranged from 68 to 127. Second, 3 of the 15 simultaneous assays showed very low numbers of sperm bound, indicating that 20% of the zonae had poor binding. Third, from 18 men who had 0% fertilization in an in vitro fertilization system using mature oocytes, evaluation of their sperm by HZA was performed. The sperm bound poorly and the 95% confidence interval was 20 sperm bound. Thus, the fertile controls should bind greater than 20 sperm to distinguish them from the infertile group in the HZA system resulting in a valid assay. CONCLUSIONS: With these guidelines, applications of the HZA may be made with greater reassurance of a valid bioassay of sperm fertilizing potential.

The hemizona assay (HZA): development of a diagnostic test for the binding of human spermatozoa to the human hemizona pellucida to predict fertilization potential.

The authors present their initial results with the hemizona assay (HZA), which was developed to predict the fertilizing potential of spermatozoa. The HZA uses the matching halves of a human zona pellucida from a nonfertilizable and nonliving oocyte, providing an internal control on zona-to-zona variability. Maximal binding of human sperm to the hemizona usually occurred after 4 to 5 hours of coincubation. Sperm from fertile men exhibited significantly higher binding capacity to hemizonae compared with sperm from men who had fertilization failure during in vitro fertilization (IVF) treatment. The HZA index is calculated as follows: (bound sperm from subfertile male) divided by (bound sperm from fertile male) X 100. These findings demonstrate that the HZA may be a useful diagnostic tool in male infertility evaluations.

Efficacy of a gonadotropin-releasing hormone agonist in the treatment of uterine leiomyomata: long-term follow-up.

The authors employed a gonadotropin-releasing hormone agonist (GnRH-a) (D-His6-pro9-NET-GnRH) to treat 19 patients with symptomatic uterine leiomyomata, by daily subcutaneous injections (4 micrograms/kg) for 6 months. After therapy, patients were followed for 6 months without any therapy. Uterine volumes were measured by serial pelvic examinations and pelvic sonography. Measurements of serum estradiol, luteinizing hormone, and follicle-stimulating hormone were used to assess treatment response. Pituitary desensitization and hypoestrogenemia were achieved in all within 8 weeks, and in 18 of 19, hypoestrogenemia was maintained for the duration. Uterine volume at the conclusion of therapy (207.5 +/- 152.7 ml) was significantly reduced in all patients when compared with pretreatment sizes (420.8 +/- 276.4, P less than 0.05). Side effects included hot flashes (78%), vaginal dryness (32%), and transient frontal headaches (55%). All patients reported partial or complete relief from their symptomatic leiomyomata. Uterine volume at the conclusion of follow-up (345.4 +/- 195.7 ml) was greater than at the conclusion of therapy. Menses resumed in all patients within 4 to 8 weeks. In conclusion, GnRH-a therapy does not provide definitive therapy for symptomatic uterine leiomyomata but is effective in reducing the size of leiomyomata as a temporary measure. Gonadotropin-releasing hormone agonist therapy may be useful as an adjunct before myomectomy or hysterectomy and deserves further investigation.

Long-acting gonadotropin hormone-releasing hormone analog used to treat uteri.

Because the size of leiomyomata uteri often decreases significantly after menopause, the authors elected to employ a long-acting gonadotropin hormone-releasing hormone analog (GnRH-alpha) (imbzl-D-His6-Pro9-Net-GnRH) to create a state of pseudomenopause in six patients with leiomyomata uteri diagnosed on the basis of pelvic examination and confirmed by pelvic ultrasonography. Patients received daily, subcutaneous injections of GnRH-alpha (4 micrograms X kg-1 X 24 hour-1) for 6 months. Uterine size (13.8 +/- 4 weeks [mean +/- standard deviation (SD), n = 6]) was determined by pelvic examination and uterine volume (533.9 +/- 394 ml [mean +/- SD, n = 6]) was determined by pelvic ultrasonography before medical therapy was begun. They observed a decrease in uterine size by pelvic examination within 4 weeks of the initiation of therapy, and all patients experienced a decrease in uterine size (9.5 +/- 4 weeks [mean +/- SD, n = 6]) (P less than 0.05) within 8 weeks of initiation of therapy. After 6 months of therapy, uterine size was 229.5 +/- 145 ml (mean +/- SD, n = 6). During treatment, plasma estrogen concentrations were assessed intermittently (every 1 to 4 weeks) and remained less than 4 pg X ml-1 throughout the period of therapy. All six patients have discontinued therapy. There has been no increase in uterine size in these patients for a period from 3 to 7 months.(ABSTRACT TRUNCATED AT 250 WORDS)