Effects of a copper-medicated intrauterine device on ovarian artery, uterine artery, and intrauterine blood flow.

AIM: To determine the effect of a copper-medicated intrauterine device (IUD) on ovarian, uterine, arcuate, radial and subendometrial Doppler-derived indices of blood flow. METHOD: 23 regularly menstruating patients requested insertion of an IUD. All patients had a copper T (Nova T) IUD inserted between days 8 and 11 of the menstrual cycle. Ovarian, uterine, arcuate, radial and subendometrial artery pulsatility indices (PIs) were assessed by transvaginal color Doppler prior to insertion between days 8 and 11 of the menstrual cycle, and after 2 months in the same period of the cycle. Ovarian, uterine, arcuate, radial and subendometrial artery PIs were considered prior to and following IUD insertion. RESULTS: No differences were recorded in any of the blood vessels sampled between pre- and post-insertion PIs. CONCLUSION: No significant change in ovarian or in uterine system vascular impedance is associated with the presence of a copper-medicated IUD.

Cytokine-mediated regulation of rat ovarian function: interleukin-1 stimulates the accumulation of a 92-kilodalton gelatinase.

It is known that the mammalian ovary possesses a complete interleukin-1 (IL-1) system replete with ligands, receptors, and a receptor antagonist. To further assess the hypothesis that IL-1 may play an intermediary role in gonadotropin-triggered ovulation, we have set out to determine whether IL-1 is capable of promoting ovarian collagenase biosynthesis, an established component of the ovulatory cascade. Untreated cultured whole ovarian dispersates from immature (25 day old) rats constitutively elaborated several collagenolytic species as assessed in a gelatin matrix. A major 72 kilodalton (kDa) gelatinase (GL) was particularly apparent. Treatment with IL-1 beta produced selective dose- and cell density-dependent increments in the accumulation of a 92-kDa GL species. Administration of an IL-1 receptor antagonist neutralized the IL-1-induced stimulation of the 92-kDa GL in a dose-dependent fashion thereby supporting the presumption that the IL-1 effect is receptor mediated. Studies of comparable cellular densities of granulosa or enriched theca-interstitial cultures demonstrated the IL-1 induced 92-kDa GL to be highly expressed in the enriched theca-interstitial but not in the isolated granulosa cell preparations. Treatment with transforming growth factor-beta 1, a putative regulator of IL-1 action, significantly attenuated IL-1-induced 92-kDa GL accumulation thereby suggesting a potential regulatory paracrine/autocrine role for this agent in ovarian gelatinase economy. Initial characterization revealed the 92-kDa GL species to be a metalloproteinase present in its proenzyme zymogenic form. Taken together, our present findings reveal the ovarian expression of a constitutive 72-kDa GL and of an IL-1-stimulated 92-kDa GL the accumulation of which is particularly marked in enriched theca-interstitial preparations. These observations, along with the demonstration of the gonadotropin-dependent preovulatory induction of ovarian IL-1 gene expression, provide strong indirect support for the view that IL-1 may be the centerpiece of an intraovarian regulatory loop concerned with the promotion of the ovulatory cascade.

Correction of hyperandrogenemia by laparoscopic ovarian cautery in women with polycystic ovarian syndrome is not accompanied by improved insulin sensitivity or lipid-lipoprotein levels.

Polycystic ovarian syndrome (PCOS) is a common disorder associated with hyperandrogenemia and infertility. Abdominal obesity, insulin resistance, and dyslipoproteinemias are other common metabolic disorders typically found in women with PCOS. The cause-effect relationship between hyperandrogenemia and insulin resistance-dyslipoproteinemia remains unclear. In this study, we have investigated the changes in androgenemia, insulin sensitivity, and plasma lipid-lipoprotein levels after laparoscopic ovarian cautery (LOC) for ovulation induction in eight infertile women with clomiphene citrate-resistant PCOS. After LOC, significant decreases in androstenedione (43%), testosterone (48%), and free testosterone (48%) concentrations were observed (P < 0.05). Glucose utilization during an euglycemic-hyperinsulinemic clamp did not change after LOC. In addition, no significant changes after the surgical procedure were observed for cholesterol, triglycerides, and apolipoprotein concentrations measured in total plasma and in different lipoprotein fractions. In conclusion, within the short duration of observation of this study, our findings demonstrate that insulin resistance and lipoprotein abnormalities associated with PCOS are not secondary to hyperandrogenemia. The clinician, therefore, must be cognizant of the persistence of these metabolic risk factors for cardiovascular disease once successful ovulation and fertility is restored, and institute appropriate monitoring, counseling, and medical intervention as required.

Cytokine-mediated regulation of rat ovarian function: interleukin-1 inhibits plasminogen activator activity through the induction of plasminogen activator inhibitor-1 (PAI-1).

Intraovarian IL-1 has recently been implicated as a mediator in the ovulatory process. Since PA activation is an established component of the ovulatory cascade, consideration was given in this report to the possibility that IL-1 may modulate ovarian PA economy. Whole ovarian dispersates from immature rats (25-27-days-old) were cultured under serum-free conditions for 48 h in the absence or presence of IL-1beta. Cellular PA activity was measured by plasminogen-dependent cleavage of 14C-labeled globin. Cells grown in the absence of IL-1 exhibited appreciable PA activity, as assessed by the cleavage of 0.074 +/- 0.026 mg [14C]-globin/5 x 10(5) cells (mean +/- SD). Exposure to IL-1 (10 ng/ml) led to a 30% reduction in cell-associated PA activity (p < 0.001). The IL-1-mediated inhibition occurred concurrently with a 10-fold increase in the ability of the corresponding conditioned media to inhibit exogenous urokinase activity. At similar cell densities of 5 x 10(5) cells/well, isolated cultures of theca and granulosa cells exhibited comparable PA activity in the absence of IL-1. However, only theca cells responded to IL-1 with inhibition of plasminogen activation and enhancement of urokinase inhibitory activity. Granulosa cells in turn failed to respond to IL-1. Both the inhibition of PA activity and the increase in urokinase inhibitory activity proved cell-density- and IL-1 dose-dependent. The IL-1-induced inhibition of urokinase was abolished by the administration of a polyclonal anti-rat PAI-1 IgG. Both effects of IL-1 were counteracted in a dose-dependent fashion by the soluble IL-1 receptor (which specifically complexes with IL-1), and by a highly-specific IL-1 receptor antagonist suggesting that the IL-1 effects are receptor-mediated. The present observations indicate that ovarian PA activity is subject to inhibition by IL-1 probably by way of PAI-1 of theca-interstitial origin. Inasmuch as IL-1 may be involved in initiating and maintaining the preovulatory cascade, the periovulatory activation of plasminogen must be accomplished by agents other than IL-1.

Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations in sibs.

A term amelic female infant was born to an apparently nonconsanguineous Arab Moslem couple. This was followed by the birth of 4 normal children. Afterwards, in 2 subsequent pregnancies, 2 amelic fetuses were diagnosed by transabdominal ultrasonography in the 18th and 12th week of gestation. Pregnancies were terminated and on autopsy both amelic fetuses had severe lung hypoplasia and aplasia of the peripheral pulmonary vessels. The first fetus also had apparently low-set ears and micrognathia, whereas the last had hydrocephaly and left cleft lip beside the lung hypoplasia and aberrant pulmonary artery. This appears to be a new autosomal recessive malformation syndrome.

Intrauterine device failure: relation to its location within the uterine cavity.

OBJECTIVE: To investigate the possible role of position of the intrauterine device (IUD) in accidental pregnancies. METHODS: We examined the location of the IUD in 97 normal women 45-60 days post-insertion, and in 25 pregnant women with the device in situ. RESULTS: A cervically located IUD was identified in seven of 97 women (7.2%) after insertion and in 13 of 25 pregnant women (52%) with the device in situ. The odds ratio for a woman with an intracervical IUD to be pregnant compared with a woman with an IUD in the uterus was 13.93 (95% confidence limits 4.13-48.96). Sonographic follow-up of the pregnant women revealed no change in IUD location during early gestation. CONCLUSIONS: We suggest that cases of failed contraceptive action of the IUD may be secondary to a malpositioned device. A sonographic survey can identify displaced devices. Reinsertion of the IUD in such cases is recommended.

Coculture with ovarian cancer cell enhances human blastocyst formation in vitro.

OBJECTIVE: To examine the effect of human embryo coculture with an ovarian cancer cell line. DESIGN: Prospective, randomized in vitro study. SETTING: University of Toronto IVF clinic at The Toronto Hospital. PATIENTS: Couples undergoing IVF who chose not to cryopreserve their spare embryos and were willing to donate spare embryos for research. INTERVENTION: Spare embryos were cultured randomly either under regular conditions with Ham's F-10 medium supplemented with 10% heat inactivated human serum (n = 189) or were cocultured in the same medium, with human ovarian epithelial cancer cells (n = 173). MAIN OUTCOME MEASURE: Blastocyst formation. RESULTS: Coculture with the cancer cell line improved the preimplantation embryo development to the blastocyst stage. There was a significant increase in the number of cavitating morulae (68%) and the proportion of embryos reaching the fully expanded blastocyst stage (39%) compared with those in standard culture medium (34% and 23%, respectively). CONCLUSION: Coculture of early cleavage stage human embryos with epithelial cancer cells markedly improves in vitro human blastocyst formation compared with standard culture conditions.

Recombinant human leukemia inhibitory factor does not enhance in vitro human blastocyst formation.

OBJECTIVE: To assess the effect of human recombinant leukemia inhibitory factor in different doses on human blastocyst formation. SETTING: A university-based tertiary referral center (The Toronto Hospital). INTERVENTIONS: Nontransferable human embryos (n = 473) at the two- to six-cell stage were obtained from patients undergoing IVF and were split randomly into five groups. Embryos in group A (n = 164) were cultured as the control group in Ham's F-10 (GIBCO-BRL, Grand Island, NY) + 10% human sera. Embryos in groups B, C, D, and E (n = 54, 78, 87, and 80, respectively) were cultured in the same medium supplemented with human recombinant leukemia inhibitory factor in four different concentrations (5, 7.5, 10, and 20 ng/mL, respectively). Morphological assessment of embryo development was recorded daily. MAIN OUTCOME MEASURE: Human blastocyst formation. RESULTS: No significant difference was detected in the rate of blastocyst formation of embryos in the study groups when compared with embryos in group A. CONCLUSIONS: This study shows that 5 to 20 ng/mL of recombinant leukemia inhibitory factor in standard medium does not enhance in vitro human blastocyst formation. It is possible that recombinant leukemia inhibitory factor may play a role at later stages of human embryogenesis and during implantation.

Ultrasonographic endometrial changes after intrauterine insemination: a comparison of two catheters.

OBJECTIVE: To determine and compare the transvaginal ultrasonographic (US) endometrial changes immediately after IUI using the Edwards Wallace (H.G. Wallace, Limited, Colchester, Essex, UK) and Tom-Cat (Sherwood Medical, St. Louis, MO) catheters. DESIGN: Prospective study. SETTING: IVF unit. PATIENT(S) AND INTERVENTION(S): Eighty-two infertile patients underwent 112 cycles of ovulation induction with IUI. Either the Edwards Wallace catheter (group 1, n = 32) or the Tom-Cat catheter (group 2, n = 80) was used for sperm insemination. The presence of an endometrial three-layer pattern before IUI was a prerequisite for inclusion in the study. After each IUI, the endometrium was reassessed by transvaginal US. MAIN OUTCOME MEASURE(S): Ultrasonographic endometrial changes, clinical pregnancy rates (PRs), complications, and patients' complaints were compared between the two groups. RESULT(S): Total destruction of the endometrial three-layer pattern was observed in 12.5% of the cycles in group 1, compared with 50% of the cycles in group 2. Clinical pregnancies occurred in 14 (12.5%) of the 112 IUI cycles. A higher PR was achieved when the endometrial three-layer pattern was preserved after IUI. The patients in group 2 had more complaints of bleeding and pain during the procedure. CONCLUSION(S): Ultrasonographic changes after IUI suggest that the Edwards Wallace catheter is significantly less traumatic to the endometrium than the Tom-Cat catheter. Although both catheters yielded the same overall PR, there was a trend indicating that sparing the endometrial three-layer pattern from damage increases the chance of conception.

In vitro fertilization outcome in the presence of severe male factor infertility.

OBJECTIVE: To assess the outcome of standard IVF treatment (nonmicromanipulated) with respect to total motile sperm number recovered by swim-up, particularly for couples with severe male factor infertility defined as total motile sperm number < 0.5 x 10(6). DESIGN: Retrospective study of patients who underwent successful oocyte retrieval in an IVF program from August 10, 1992 to December 31, 1993. SETTING: A university-based tertiary referral center (The Toronto Hospital). PATIENTS: All cycles (n = 672) were divided into four groups according to total motile sperm number recovered using standard swim-up: group 1, total motile sperm number < or = 0.50 x 10(6); group 2, total motile sperm number between 0.51 and 1.00 x 10(6); group 3, total motile sperm number between 1.01 and 1.50 x 10(6); and group 4, total motile sperm number > or = 1.51 x 10(6). All patients received the same controlled ovarian hyperstimulation protocol, which consisted of a GnRH analog flare-up followed by parenteral menotropins. Clinical and cycle characteristics in the four groups were analyzed and outcome was evaluated. RESULTS: There was no significant difference in clinical and cycle characteristics between the groups. The uniformity of the groups justified analysis of their outcome. A fertilization rate of 21.5% was achieved in couples with severe male factor (group 1). Fertilization rate and number of embryos transferred increased directly with the total motile sperm number. There was no significant difference in implantation rate per embryo between the groups. CONCLUSIONS: The results in couples with severe male factor infertility compare favorably with monospermic fertilization rates reported in the literature using partial zona dissection and subzonal insertion but is lower than with intracytoplasmic sperm injection. Therefore, we believe that couples with severe male factor infertility should be considered for standard IVF, as long as adequate total motile sperm can be recovered (100 x 10(3) per dish). If intracytoplasmic sperm injection is available, it should be offered to these couples.

Ovarian response to recombinant human follicle-stimulating hormone in luteinizing hormone-depleted women: examination of the two cell, two gonadotropin theory.

OBJECTIVE: To evaluate the relative contribution of FSH to ovarian estrogen production. DESIGN: Nonrandomized, prospective study. SETTING: University of Toronto teaching hospital reproductive biology unit. PATIENTS: Five women who had been treated with depot GnRH agonist with hormonal add-back for 4 to 48 months and who were confirmed to be gonadotropin depleted by both bioassay and RIA. INTERVENTIONS: Subjects received 75 IU SC recombinant human FSH daily for 7 days followed by 150 IU daily for 7 days and 225 IU daily for the third week. MAIN OUTCOME MEASURE: Serum steroid determination and vaginal sonography for follicle size and endometrial thickness were performed serially and follicular fluid hormone levels were measured in two subjects. RESULTS: Bioactive LH and FSH activity were less than the detection limit of the assay (0.1 mIU/mL; conversion factor to SI units, 1.00 for LH and FSH) before recombinant FSH treatment in all five women. In all subjects, at least one preovulatory follicle developed by the end of two to three weeks. Endometrial thickness increased to between 7 and 9 mm in four women. Mean serum E2 in the five subjects increased from 17 pg/mL (range: 5 to 33 pg/mL; conversion factor to SI unit, 3.671) at baseline to 230 pg/mL (range: 37 to 489 pg/mL) at the end of the study. Follicular fluid E2 concentrations ranged from 44,296 to 69,367 pg/mL in the four follicles aspirated. CONCLUSION: Our results indicate that LH is not necessary for ovarian E2 production. We speculate that the granulosa cells, in the absence of detectable LH bioactivity, can use circulating adrenal androgens or constitutive or FSH-stimulated thecal androgens, to produce intrafollicular E2.

Transfer of embryos from yeast-colonized dishes.

OBJECTIVE: To report yeast colonization in IVF dishes, where ET was carried out, and the IVF outcome was not compromised. DESIGN: Retrospective study of patients who underwent IVF cycle during the last 4 years. SETTING: In vitro fertilization program at the Shaare-Zedek hospital in Jerusalem. PATIENTS: Five couples who underwent standard IVF cycles and whose dishes were colonized with yeast. After thorough discussion ET was carried out. RESULTS: Although colonized with yeast, the quality of the embryos was not compromised. One to three of these embryos were transferred. All five women conceived. CONCLUSIONS: In vitro fertilization outcome is not necessarily compromised by yeast colonization. Nevertheless, the possible teratogenic effect of yeast on embryos has not been investigated and research is required to address this concern.

The effect of ethinyl estradiol on endometrial thickness and uterine volume during ovulation induction by clomiphene citrate.

OBJECTIVE: To assess the deleterious effect of clomiphene citrate (CC) on the development of the endometrium and its improvement by the addition of ethinyl estradiol (E2). PARTICIPATING PATIENTS: Infertility-treated patients, monitored for induction of ovulation or timing of insemination (control group). DESIGN: We studied four groups of women during an ovulatory cycle with various treatment schedules. Group 1: untreated patients; group 2: patients treated by CC; group 3: patients treated by CC + ethinyl E2; group 4: patients treated by human menopausal gonadotropin. Follow-up of the patients was done by vaginal ultrasonography and measurements of blood E2. RESULTS: In the group treated by CC, both endometrial thickness and uterine volume growth during the follicular phase were lower as compared with untreated controls and menotropin-treated patients. The addition of ethinyl E2 to these patients reversed this deleterious effect of CC without interfering with ovulation. CONCLUSION: Ethinyl E2 may reverse the deleterious effect of CC on endometrial development during the follicular phase.

Determination of IgG subclasses in patients with pemphigus with active disease and in remission.

IgG subclasses were determined in perilesional skin of 13 patients with pemphigus with active disease and of 14 patients in a state of clinical remission. Using indirect immunofluorescence technique, frozen sections were incubated with mouse monoclonal antihuman IgG1, IgG2, IgG3, and IgG4 followed by a second incubation with fluorescein isothiocyanate-conjugated goat antimouse IgG. The results showed that among patients with active disease, IgG1 was found in all of them and IgG4 in 85%, while IgG2 and IgG3 were found in 54% and 77%, respectively. For patients in remission the most common subclass was IgG4 in 79% of patients, and in a decreased order IgG1, 50%; IgG3, 29%; and IgG2, 14%. It appears that IgG1 and IgG4 are predominant among patients with active lesions. IgG1 seems to be the most sensitive indicator for activity of the disease. IgG4, normally found in the lowest concentration in human serum, is the most common subclass in patients who are in remission. IgG3 and C3 may have a predictive value for remission.

The management of intrauterine devices following uterine perforation.

The generally accepted indications for removal of an intra-abdominal intrauterine device (IUD) are: a) a closed variety of IUD, b) medicated IUDs with copper or hormone release, and c) a medico-legal or psychological problem. A perforated IUD can be left in the peritoneal cavity if it is made of non-irritating plastic. The copper IUD causes adhesions, but these lead to few cases of serious complications. The reason for removal of the IUD stems only from the fear of adhesion formation. Our experience, supported by the literature, leads us to believe that this indication should no longer be accepted.

PIP: Management of 11 cases of translocated IUDs, from 1978-1986, at the Hadassah University Hospital, Jerusalem, suggested that leaving the IUD in place is less risky than laparotomy. The IUDs were 4 Lippes loops, 4 Nova Ts, and 3 MLCu 250s, inserted at postpartum Weeks 6-18. The indications were missing threads in 5 cases and pregnancy in 6. Women with missing threads were managed by ultrasound and plain x-ray, and a uterine sound if results were inconclusive. Pregnant women were terminated if they had requested, and the IUD was removed. If the IUD was not found, ultrasound and x-ray were done. IUDs were removed by laparoscopy if possible (3 cases), or laparotomy (8 cases). In 2 cases ultrasound located the IUDs in the uterus incorrectly. IUDs were embedded in the omentum in 4 cases, adherent to the broad ligament in 3 cases, and free in the peritoneum without an adhesion in 1 women. The 9 cases with adhesions did not have bands of adhesions. This experience suggests that adhesions form briefly, and do not develop further. Since removal of the IUD does not cause adhesions to dissolve, but does confer the risks of laparotomy, it is suggested that open 3rd generation IUDs should not be removed unless there are clinical symptoms such as bowel obstruction.

Prolongation of the latent period in patients with premature rupture of the membranes by avoiding digital examination.

Fifty three women with PROM between 26 and 34 weeks of gestation were examined. Twenty five women (group A) underwent one digital examination for cervical assessment while in 28 women (group B) the cervix was evaluated by speculum. No pelvic examinations were performed throughout the latent period. The latent period increased from 3.1 days in group A to 9.5 days in group B (P less than 0.005). Chorioamnionitis developed in 24% in group A and in 18% in group B (N.S.).

Sinusoidal fetal heart rate pattern due to massive feto-maternal transfusion.

A 30-year-old woman presented with mild abdominal discomfort and decreased fetal movements in the 34th week of her third pregnancy. Fetal monitoring revealed a sinusoidal heart rate pattern, and abdominal delivery was promptly performed, with the newborn having a hematocrit of 7% due to massive fetomaternal transfusion. Fetal resuscitation was followed by a favorable outcome. The sinusoidal heart rate is discussed, with emphasis on the need for proper and prompt recognition of its significance.

[IUD-associated abdominopelvic actinomycosis].

Abdominopelvic actinomycosis associated with the use of an intrauterine contraceptive device (IUD) is described. The diagnosis is usually made after exploratory laparotomy for severe abdominal pain and signs of an acute abdomen, or for prolonged lower abdominal pain and findings consistent with pelvic malignancy. 3 women aged 33, 44 and 52 years, respectively, are presented.

PIP: 3 cases of IUD-related abdominopelvic actinomycosis diagnosed after surgery are described. A 44-year old woman was admitted with high fever and diffused, strong abdominal pain. She had had an IUD for 4 years. Hypersensitivity all over the pelvis, an enlarged uterus, and peritoneal irritation were found upon vaginal examination. Opening the peritoneum yielded 1 liter of pus, a 6 cm diameter abscess of the right adnexa, and a myomatous uterus in 12 weeks of gestation. The uterus and the right adnexa were removed. Histology confirmed actinomycosis. Penicillin was given iv for 6 weeks, and after release she took oral penicillin for 4 more months. A 33-year old woman was admitted with high fever and excruciating pain in the lower right abdomen that had lasted on and off for months. She had had an IUD for 3 years. Vaginal examination revealed a hypersensitive uterus. enlarged right adnexa, and a firm mass between the vagina and the rectal shelf. Surgery showed the omentum attached to the sigmoid colon and the right fallopian tube with an abscess of 5 cm with cysts. The growth was resected, and the cysts were opened. She received iv erythromycin for 3 weeks and then orally for 2 months leading to full recovery. A 52-year old woman was hospitalized for hysterectomy. She had had abdominal pain radiating to the back for 1 year. She had had an IUD for 15 years. A myomatous uterus in 15 weeks of gestation was detected. Surgery revealed a 15 cm size myomatous uterus with an abscess of 6 cm around it. The uterus, the left adnexa, and the abscess were resected. Histology indicated actinomycosis. She received iv ampicillin for 1 month, and scar tissue from the abscess was treated with oral penicillin for 1 month. Cervical actinomycosis was found in 1-30% of women wearing IUDs. Diagnosis requires histopathological examination. The symptomless presence of cervical actinomycosis may require the temporary removal of the IUD and antibiotic treatment.