The safety and effectiveness of a new hysteroscopic method for permanent birth control: results of the first Essure pbc clinical study.

BACKGROUND: Current methods of female surgical sterilisation require incisional surgery, general anaesthesia and a prolonged recovery time. We studied the safety and effectiveness of Essure pbc, a minimally invasive, transcervically placed micro-insert that occludes the Fallopian tubes, resulting in permanent female contraception. Device under study: The Essure pbc implant is a dynamically expanding micro-insert which is placed in the proximal section of the Fallopian tube using a modified minimal access technology for cannulating the tube. STUDY POPULATION: Women aged 21-43 seeking permanent birth control. METHODOLOGY: Essure pbc micro-inserts were inserted into the proximal portion of the Fallopian tubes under hysteroscopic visualisation with intravenous sedation or paracervical block. RESULTS: Bilateral device placement was achieved in 111 of 130 (85%) women who underwent device placement attempts. Women found the device placement procedure to be highly acceptable. Of women wearing the device for up to two years rate, 97% rated it to be very good to excellent. There have been no pregnancies reported in 1894 woman-months of effectiveness. Adverse events preventing women from relying on Essure pbc were < 5%. DISCUSSION: This first clinical trial showed the Essure pbc method of permanent contraception to be safe and highly acceptable to women. Experience and improvements to the delivery system should increase overall micro-insert placement rates. CONCLUSION: The Essure pbc method of permanent contraception is an exciting alternative to vasectomy or laparoscopic sterilisation that does not require general anaesthesia or incisions.

New methods for transcervical cannulation of the fallopian tube.

Technological advances have led to major improvements in the design and application of Fallopian tube cannulation devices using the transcervical approach. Presently such cannulation systems are being used to overcome infertility disorders. These transcervical access systems are now able to displace debris that may block the tube, break down intraluminal adhesions or place egg, sperm or embryos in the tube to facilitate conception. Conversely, these same or modified devices could be used to place sclerosing agents or occlusive devices within the Fallopian tubes using similar transcervical access technology. Transcervical delivery systems incorporating a very fine endoscopic fiber have also been developed to visibly assess the inside lumen of the Fallopian tube using a transcervical approach. Such a system could be used to accurately identify specific sites in the tube for placement of such devices. The potential for placing permanent or temporary devices in the tube and the option of reversible sterilization may become a possibility in the future. One of the biggest obstacles against a wide distribution of these devices, particularly in third world countries, will be cost and the relative technical complexity in using them. These factors will need to be addressed more carefully in assessing the overall strategy of population control. The pressure on governments and international agencies to place more resources into population control may facilitate the accelerated development, application and cost containment of these new devices and delivery systems.

[Falloposcopy--a new method for evaluation and treatment of infertility due to tubal factors].

Tubal factors cause infertility in about a third of cases. With current diagnostic techniques, such as laparoscopy and hysterosalpingography, only a fraction of the causes of tubal infertility can be diagnosed and in many cases misdiagnosis results. Newer methods, such as ampullosalpingoscopy enable examination of the fimbria and ampullar segment of the fallopian tube, but the examination of the proximal tube, in which 10-20% of occlusions occur, is still impossible. We describe a new diagnostic technique, falloposcopy. It involves the transuterine insertion of a fiber optic device into the fallopian tube through a hysteroscope. This technique enables direct visualization of all segments of the fallopian tube, as well as removal of intratubal debris or adhesions. Using falloposcopy, a new grading method for tubal disease has been developed. We describe the results of 129 falloposcopic procedures in 82 women. Following falloposcopy, women with mild to moderate disease, according to the new classification, have conceived without further therapy during a follow-up period of up to 3 years. Falloposcopy may aid in differentiating between patients suitable for tubal surgery and those who should be referred for in vitro fertilization.

A prospective randomized comparison of luteal phase versus concurrent follicular phase initiation of gonadotropin-releasing hormone agonist for in vitro fertilization.

OBJECTIVE: To compare the effects of gonadotropin-releasing hormone agonist (GnRH-a) initiation either preceding or concurrent with controlled ovarian hyperstimulation (COH) in patients undergoing in vitro fertilization-embryo transfer (IVF-ET). DESIGN: Fifty-five patients were prospectively randomized to receive either GnRH-a on cycle day 21 before COH until ovarian suppression was achieved (group I) or GnRH-a concurrently with COH commencing on cycle day 3 (group II). MAIN OUTCOME MEASURES: Serum gonadotropin and ovarian steroid hormone levels, as well as fertilization, spontaneous abortion, and live birth rates. RESULTS: Twenty-six patients in group I and 29 patients in group II underwent COH for IVF-ET. Patients in group II had significantly higher serum luteinizing hormone, progesterone, and testosterone levels during stimulation with human menopausal gonadotropins (hMG) before oocyte retrieval (P < 0.05). Despite similar fertilization, biochemical, and clinical pregnancy rates, the spontaneous abortion rate was higher in group II (5/6) compared with group I (1/7) (P < 0.05). Thus, the live birth rate/retrieval for group I was 6 of 24 (25%) as compared with that of group II, which was 1 of 26 (3.8%) (P < 0.05). CONCLUSIONS: The initiation of GnRH-a in the follicular phase concurrently with hMG is associated with evidence of premature luteinization, hyperandrogenemia, and poorer pregnancy outcome compared with luteal phase administration of GnRH-a before hMG for IVF-ET.

Falloposcopic identification of a fimbrio-ovarian mucus connection as a possible mechanism for tubal oocyte capture.

Falloposcopy combined with laparoscopy was performed in 11 women during the late follicular phase of spontaneous menstrual cycles, and a preovular follicle was confirmed to be present in each case. The fimbrial end of the tube and the ipsilateral ovary containing the preovular follicle were suspended in a fluid environment of 200 ml of lactated Ringer's solution which acted as a support medium for visualization of tubal mucus and facilitated the endoscopy procedure. As the falloposcope was passed through the fimbrial opening, it was observed to carry clear, elastic and filamentous strands of mucus material from within the distal tubal lumen in 4 of 11 procedures. As these mucus strands were carried on the tip of the falloposcope to touch the surface of the ovary containing the preovular follicle, they attached, on contact, in all cases. The fimbrio-ovarian mucus bridge created was quite strong and could be stretched for up to 7 mm before it detached from the ovarian surface. The mucus attachment appeared to be equally secure over the preovular follicle and adjacent ovarian surfaces. These fimbrio-ovarian mucus connections, which have a high affinity for ovarian surface attachment about the time of ovulation, may play an important role in securing tubal oocyte capture in humans.

Falloposcopic observations of endotubal isthmic plugs as a cause of reversible obstruction and their histological characterization.

Eighty falloposcopies were performed in fallopian tubes of women with suspected tubal disease. In three falloposcopies (4%), isthmic plugs were observed occluding the entire isthmic lumen. In all cases these plugs were mobilized by falloposcopic-directed, selected tubal cannulation and aquadissection techniques. Restoration of tubal patency, verified by concurrent chromopertubation under laparoscopic monitoring was achieved in all cases. On one occasion, the isthmic plug was mobilized and identified on the fimbria, and tubal patency was confirmed. When this plug was retrieved and examined histologically, it was found to consist of a cast of debris containing aggregates of histiocyticlike cells of endometrial stromal or mesothelial origin. The genesis of these plugs is unknown. In another subgroup, white to yellow mucus like fragments were observed within the intramural and isthmic lumen during a further 8 of 80 falloposcopies (10%). Whether these mucus like fragments are of physiological or pathophysiological significance remains to be determined. Objective demonstration that isthmic plugs can cause reversible proximal tubal obstruction (PTO) has been achieved using falloposcopy. Falloposcopy offers the diagnostician the ability to objectively classify the cause of PTO. A useful falloposcopic classification and scoring system of tubal lumen lesions has been utilized and is described.

Removal of cornual polyps with flexible hysteroscopy and a wire basket. A case report.

The hysteroscopic removal of large uterine polyps often can assist infertile women in conceiving. This report describes the removal of bilateral cornual polyps in a diethylstilbestrol-deformed, T-shaped uterus using a flexible operating hysteroscope and an 0.8-mm ureteral wire stone basket.

Regulation of cholesterol side-chain cleavage and 17 alpha-hydroxylase/lyase activities in proliferating human theca interna cells in long term monolayer culture.

In this report we describe the development and characterization of a long term culture system to study regulation of the expression of 17 alpha-hydroxylase, cholesterol side-chain cleavage, and 3 beta-hydroxysteroid dehydrogenase in human theca interna cells. Conditions have been established for the dispersal, growth, freezing, and storage of functional human theca interna cells isolated from preovulatory follicles of women undergoing laparoscopy for gamete intrafallopian tube transfer and in vitro fertilization procedures. Theca interna cells grown under these conditions have a doubling rate of 28-32 h and are morphologically distinct from human granulosa cells grown under the same conditions. Theca interna cells were grown, passed for successive passages, and transferred into serum-free medium containing forskolin, hCG, LH, or cAMP analogs. There was a time- and dose-dependent increase in 17 alpha-hydroxylase activity and progesterone synthesis from endogenous precursors. Added pregnenolone was converted to 17 alpha-hydroxypregnenolone, which was further converted primarily to dehydroepiandrosterone and, to a much lesser extent, androstenedione. Progesterone was converted to 17 alpha-hydroxyprogesterone and 16 alpha-hydroxyprogesterone. In studies using 17 alpha-hydroxyprogesterone as substrate, no metabolism to androstenedione or any other product was detectable. Similarly, 4-pregnen-20 alpha-ol-one (20 alpha-dihydroprogesterone) was not metabolized to any detectable products. Northern analysis performed on total RNA obtained from forskolin-stimulated theca interna cultures verified that the increase in 17 alpha-hydroxylase activity was associated with a corresponding increase in levels of mRNA specific for 17 alpha-hydroxylase cytochrome P-450. Message levels for cholesterol side-chain cleavage P-450 were similarly increased in cells treated with forskolin. No detectable mRNA encoding aromatase cytochrome P-450 was discerned. This procedure for the preparation and study of proliferating human theca internal cells provides an opportunity to study regulation of the expression of steroidogenic enzymes and other cellular processes unique to human ovarian cells.

Gonadotropin and estradiol levels during ovarian stimulation in women treated with leuprolide acetate.

Levels of FSH, LH, and estradiol (E2) were measured in the serum of 209 gonadotropin-releasing hormone analogue-treated women and in 202 control subjects during the final 5 days of ovarian stimulation in our in vitro fertilization program. Levels of FSH and E2 in serum of gonadotropin-releasing hormone analogue-treated subjects significantly exceeded control values during the sampling period, whereas LH levels were significantly lower. Concentrations of E2 in serum of gonadotropin-releasing hormone analogue-treated and control subjects were similar when corrected for differences in numbers of follicles aspirated at oocyte retrieval (mean of 8.9 and 7.2 follicles per subject, respectively). Pregnancy rates by diagnostic ultrasound were 18 and 11%, respectively, a statistically significant difference.

Levels of steroid and protein hormones in antral fluids of women treated with different combinations of gonadotropins, clomiphene citrate, and a gonadotropin-releasing hormone analog.

Levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, progesterone (P), and total protein in follicular fluids collected from 18 patients pretreated with a gonadotropin-releasing hormone analog (GnRHa), in association with human menopausal gonadotropin (hMG) and FSH, were compared with values for 69 patients treated with FSH, hMG, FSH/hMG, or clomiphene citrate (CC)/hMG in an in vitro fertilization (IVF) program. The authors have established a number of significant differences in chemical and physical properties of follicular fluids of patients treated by different regimen, and concur with earlier evidence that the volume of a follicle, and its P and total protein content, are related to the maturity of the oocyte nested within the follicle. Overall, however, differences in concentrations of gonadotropins in follicular fluids between groups were not consistent with differences in follicular fluid steroid levels, and levels of immunoactive gonadotropins in follicular fluids were not in accord with dosages of exogenous immunoactive gonadotropin administered during hyperstimulation. The most favorable outcomes of IVF (greater than 70% of oocytes fertilized) were established with oocytes collected from patients treated with FSH only or with CC/hMG, and patients treated with FSH only yielded the highest average number of oocytes which fertilized in vitro (6.2 per patient).

The effect of transferring pronuclear embryos on pregnancy outcome after in vitro fertilization.

In a prospective clinical trial the pregnancy rate in patients matched for infertility status, degree of hyperstimulation, and number of oocytes recovered was unaffected by whether embryos were transferred while still pronuclear (day 1) or after they had undergone cleavage (day 2). The pregnancy rates per transfer were 27% and 22%, respectively, for the two transfer times. Unlike results of a previous study, no difference was detected in the outcome of pregnancies from the two groups.

Pregnancy-related chemotactic activity of human follicular fluid.

We measured chemotactic activity in 238 follicular fluids (FF) aspirated from 45 women who had undergone ovarian stimulation with a combination of clomiphene citrate and human menopausal gonadotropin for oocyte retrieval, in vitro fertilization, and embryo transfer. Fifteen of the treatment cycles resulted in pregnancy. The mean chemotactic activity, measured as the distance in microns granulocytic leukocytes migrated through a 3.0-micron membrane, was significantly higher in FF from conceptual cycles, compared with nonconceptual cycles. Serum chemotactic activity was significantly lower in conceptual cycles, compared with nonconceptual cycles. A chemotactic gradient appears to exist between the peripheral circulation and the ovarian follicle. The gradient favors the follicle in conceptual cycles, as indicated by the chemotactic quotient (the ratio of chemotactic activity of FF to serum). In conceptual cycles the chemotactic quotient was 1.7 +/- 0.17, compared with 0.7 +/- 0.03 for nonconceptual cycles. The presence of leukocyte chemotactic factor in FF appears to discriminate prospectively with a 90% degree of confidence between conceptual and nonconceptual in vitro fertilization and embryo transfer cycles.

Evidence for a hypothalamic site of action of clomiphene citrate in women.

To examine the site of action of clomiphene citrate (CC), LH and FSH pulsatile amplitude, frequency, and responsiveness to GnRH (10 micrograms, iv) were studied in 11 women during the early follicular phase of the menstrual cycle. Six women received CC (150 mg/day) on cycle days 2, 3, and 4, while 5 women received placebo tablets. Blood samples were drawn at 10-min intervals for 8 h before and after the treatment regimen on cycle days 2 and 5, respectively. All women treated with CC had multiple follicular development, as determined by ultrasound. Peripheral levels of estradiol did not change after CC treatment, while progesterone levels decreased slightly. Mean levels of LH increased from 7.5 +/- 0.9 (+/- SEM) to 10.7 +/- 1.4 mIU/ml (P less than 0.05), and FSH increased from 6.7 +/- 0.9 to 10.1 +/- 0.9 mIU/ml (P less than 0.01). After exposure to CC, the pulse frequency of LH during an 8-h period increased significantly (3.3 +/- 0.7 on day 2 vs. 6.8 +/- 0.8 on day 5; P less than 0.01), while the pulse frequency of FSH increased from 3.8 +/- 0.6 to 5 +/- 1.4, as determined by computer pulse analyses. The pulse amplitude of LH and FSH was not significantly altered. In the placebo-treated group, neither pulse amplitude nor pulse frequency changed significantly between cycle days 2 and 5. Pituitary sensitivity to exogenous GnRH did not change after CC treatment. Since the pulsatile frequency of LH is governed by hypothalamic influences, these findings provide compelling evidence for a hypothalamic site of action for CC, probably by inducing an increase in the frequency of GnRH secretion.

The effect of porcine relaxin vaginally applied at human embryo transfer in an in vitro fertilization programme.

It has been suggested that the polypeptide hormone relaxin is an early pregnancy factor which facilitates implantation and pregnancy maintenance. To test this hypothesis a double blind randomized placebo controlled trial was conducted where 2 mg purified porcine relaxin or distilled water was given in a vaginal gel on the day of embryo transfer and again 3 days later in a human in vitro fertilization (IVF) programme. There were 96 patients in the randomized trial and 73 patients who were treated concurrently in the same IVF programme acted as a further control group. Of the 51 patients who received relaxin, 10 pregnancies were confirmed and 8 continued successfully. In the 45 patients treated with placebo 10 pregnancies were also confirmed and 6 continued successfully. Amongst the 73 patients concurrently treated outside the trial 14 achieved a pregnancy and 10 continued to term. Thus, porcine relaxin given in these circumstances in a human IVF programme did not appear to improve or interfere with the pregnancy rate. Possible factors that affected the implantation rates in this trial are discussed.

Endocrinology of ovarian stimulation for in vitro fertilization.

Understanding of the endocrinology of in vitro fertilization has advanced rapidly in the past 5 years. Despite a multitude of ovarian stimulation regimens a particular regimen has not demonstrated a marked superiority. In principle the achievement of high FSH levels during the early follicular phase to recruit a maximum number of follicles with a tolerable degree of asynchrony for final maturation is confined to a limited time span or 'FSH window' of about 3 to 4 days before negative E2 feedback induces below-threshold FSH levels, thereby condemning all subsequent follicles in that cycle to atresia. It appears that one can widen and/or amplify the 'FSH window' too far from gross hyperstimulation resulting in the recruitment of many follicles with an intolerable degree of asynchrony. This may lead to a defective endocrine environment for the oocytes contained within these follicles or an abnormal luteal environment and an increased frequency of fertilization, cleavage and implantation failure. Whichever regimen is used, the stimulation should ideally be sufficient to promote the development of at least 3 follicles beyond 18mm diameter at the time of OPU. This can be expected to result in at least 2 embryos to be available for transfer. Monitoring of follicular response by a combination of E2 and ultrasonic parameters is recommended so that the administration of HCG is given close to the anticipated endogenous rise of LH. This can be achieved by detecting a reduction in the rate of E2 rise (to plateau).(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro fertilization and embryo transfer program, Department of Obstetrics and Gynecology, University of Adelaide at the Queen Elizabeth Hospital, Woodville, South Australia.

A review is presented summarizing the in vitro fertilization experience at the University of Adelaide, Australia. Initial attempts utilizing the normal cycle were unsuccessful in obtaining a pregnancy. Since 1982 the overall ongoing pregnancy rate has been 21% per embryo transfer, 16% per laparoscopy, and 12% per treatment cycle. A detailed description of presently utilized methodology is presented.