Engineering challenges for accelerated fusion demonstrators.

There are several programmes within the fusion community that are engaged in the design of fusion devices to follow the International Thermonuclear Experimental Reactor (ITER), referred to as 'demonstrators'. These programmes have identified many issues over the past decade, and research now concentrates on optimizing the combination of systems against a set of Key Performance Indicators (KPI) which may vary between programmes. While the return on investment in and experience from ITER is seen as an important factor in this research there are significant differences in the operational conditions and KPI of demonstrators that generate additional problems requiring different solutions. Among these problems are the necessary use of uncommon materials for structural and functional purposes, the impact of the availability KPI on basic machine design, configuration and component lifetime and the integration of the tritium fuel and thermodynamic cycles. These raise issues of component manufacture and standards and of resource availability in the required quantities and quality that are independent of device size and design. Interpreting 'accelerating fusion' in a wider sense, the impact of these issues, analysed in respect of developmental timescales, shows that a strategy of early engagement with the industrial supply chain and the development of computational engineering testing and verification will be essential to prevent prolonged timescales to fusion progress. This article is part of a discussion meeting issue 'Fusion energy using tokamaks: can development be accelerated?'

Sheath structure in negative ion sources for fusion (invited).

In fusion negative ion sources, the negative ions are formed on the caesiated plasma grid predominantly by hydrogen atoms from the plasma. The space charge of the negative ions leaving the wall is not fully compensated by incoming positive ions and at high enough emission a virtual cathode is formed. This virtual cathode limits the flux of negative ions transported across the sheath to the plasma. A 1D collisionless model of the sheath is presented taking into account the virtual cathode. The model will be applied to examples of the ion source operation. Extension of the model to the bulk plasma shows good agreement with experimental data. A possible role for fast ions is discussed.

Embryo transfer: techniques and variables affecting success.

OBJECTIVE: To review the literature on the variables affecting embryo transfer success or failure and to define technical factors associated with optimal outcome. DESIGN: Literature review. RESULTS: Avoidance of blood, mucus, bacterial contamination, excessive uterine contractions, and trauma to the endometrium is associated with optimal pregnancy and implantation rates after transcervical embryo transfer. A trial transfer, ultrasonographic guidance, and use of "soft" catheters appear to facilitate successful embryo transfer. CONCLUSION: An understanding of the variables associated with embryo transfer success together with adherence to techniques shown to facilitate atraumatic embryo transfer will enhance the efficiency of IVF by maximizing embryo implantation.

Laparoscopic management of hydrosalpinges before in vitro fertilization-embryo transfer: salpingectomy versus proximal tubal occlusion.

OBJECTIVE: To compare ovarian response and IVF-ET cycle outcome in patients with hydrosalpinges managed by either laparoscopic salpingectomy or proximal tubal occlusion. DESIGN: Retrospective analysis. SETTING: Tertiary-care assisted reproductive technology program. PATIENT(S): One hundred four consecutive fresh IVF-ET cycles in 94 patients with tubal-factor infertility. INTERVENTION(S): Laparoscopic salpingectomy (group 1: 35 cycles) or bipolar proximal tubal occlusion (group 2: 17 cycles), controlled ovarian hyperstimulation, and IVF-ET. Control groups consisted of both tubal-factor patients without hydrosalpinges (group 3: 37 cycles) and those with prior bilateral tubal ligation for sterilization (group 4: 15 cycles). MAIN OUTCOME MEASURE(S): Uterine artery Doppler flow, controlled ovarian hyperstimulation response, and implantation and clinical pregnancy rates. RESULT(S): There were no differences in mean uterine artery pulsatility indices or ovarian response among any of the groups. A trend toward a higher cycle cancellation rate in group 1 did not approach statistical significance. Clinical pregnancy and implantation rates were not significantly different between group 1 (57.1%, 29.2 +/- 5.9%, respectively) and group 2 (46.7%, 19.4 +/- 6.1%, respectively) or compared with those of controls. CONCLUSION(S): [1] Management of hydrosalpinges by laparoscopic salpingectomy or bipolar proximal tubal occlusion yielded statistically similar responses to controlled ovarian hyperstimulation and IVF-ET cycle outcome. [2] The latter approach may be preferable in patients who present with dense pelvic adhesions and easy access only to the proximal fallopian tube.

Impact of intramural leiomyomata in patients with a normal endometrial cavity on in vitro fertilization-embryo transfer cycle outcome.

OBJECTIVE: Assess the impact of intramural uterine leiomyomata and a normal endometrial cavity on IVF-ET cycle outcome. DESIGN: Retrospective case-controlled analysis. SETTING: Tertiary-care-assisted reproductive technology program. PATIENT(S): Three hundred ninety-nine consecutive fresh IVF-ET cycles were performed in patients with a normal precycle diagnostic hysteroscopy; patients were divided into four groups. Group 1: positive leiomyomata, age <40 years (n = 51 cycles); group 2: negative leiomyomata, age <40 years (n = 57 cycles); group 3: positive leiomyomata, age > or =40 years (n = 22 cycles); group 4: negative leiomyomata, age > or =40 years (n = 59 cycles). A subgroup of all group 2 patients aged 35-39 (group 2A, n = 113 cycles) was also evaluated as an additional control. INTERVENTION(S): Controlled ovarian hyperstimulation, IVF-ET. MAIN OUTCOME MEASURE(S): Implantation (IR), live birth (LBR) rates. RESULT(S): There were no significant differences in LBR among age-matched controls: group 1 (49%) versus 2 (57.5%) or 2A (57%) and group 3 (40.9%) versus 4 (32.2%). IR was significantly lower in group 1 (21.4%) versus 2 (33.3%) or 2A (33.9%) but not in group 3 (17.5%) versus 4 (11.6%). Implantation did not correlate with either mean leiomyoma diameter or volume. CONCLUSION(S): [1] LBR was not affected by the presence of intramural leiomyoma in IVF-ET patients with hysteroscopically normal endometrial cavities. [2] A significant decrease in IR was only noted in patients <40 years old. [3] Given the relatively high LBR in all groups, prophylactic surgical intervention cannot be justified, but precycle hysteroscopy evaluation is recommended.

Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques.

OBJECTIVE: To assess the efficacy of various controlled ovarian hyperstimulation (COH) regimens in the prior poor-responder patient preparing for assisted reproductive techniques. DESIGN: English-language literature review. PATIENT(S): Candidates for assisted reproductive techniques who had been defined as having a prior suboptimal response to standard COH regimens. INTERVENTION(S): A variety of regimes are reviewed, including increased gonadotropin doses, change of gonadotropins, adjunctive growth hormone (GH), luteal phase (long) GnRH agonist (GnRH-a) initiation, early follicular phase (flare) GnRH-a initiation, low-dose luteal phase (ultrashort) GnRH-a initiation, progestin pretreatment, and microdose flare GnRH-a initiation. MAIN OUTCOME MEASURE(S): Maximal serum E(2) levels, follicular development, dose, and duration of gonadotropin therapy, cycle cancellation rates, oocytes retrieved, embryos transferred, and clinical and ongoing pregnancy rates. RESULT(S): A lack of uniformity in definition of the poor responder and of prospective randomized trials make data interpretation somewhat difficult. Of the varied strategies proposed, those that seem to be more uniformly beneficial are microdose GnRH-a flare and late luteal phase initiation of a short course of low-dose GnRH-a discontinued before COH. CONCLUSION(S): No single regimen will benefit all poor responders. General acceptance of uniform definitions and performance of large-scale prospective randomized trials are critical. Development of a reliable precycle screen will allow effective differentiation among normal responders, poor responders, and those who will not conceive with their own oocytes.

Role of GnRH agonists in managing proximal fallopian tube obstruction.

OBJECTIVE: To assess the response of proximal fallopian tube obstruction to a medically induced hypoestrogenic state after control for spasm at the uterotubal ostium. STUDY DESIGN: This was a prospective, randomized, placebo-controlled, pilot study in a tertiary care, university-affiliated infertility practice. Twenty-one infertile women with unilateral or bilateral proximal tubal obstruction previously diagnosed by standard hysterosalpingography or laparoscopic chromotubation were randomized into two groups in a 2:1 design. Group I, 14 patients (27 occluded tubes), was administered a depot preparation of the gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate, 3.75 mg intramuscularly every 28 days. Group II, seven patients (11 occluded tubes), was administered a placebo. Follow-up hysterosalpingography was performed after administration of the antispasmodic glucagon within four weeks of completion of the protocol. RESULTS: Evidence of ovarian suppression was confirmed within four weeks in group I. A trend toward higher posttherapy patency rates was noted in group I (74.7% vs. 40%). The lack of statistical significance may have been a function of sample size. Similarly, spontaneous intrauterine pregnancy rates were also higher in GnRH agonist-treated patients (35.1% vs. 16.6%, P < .05). Tubal patency rates were significantly greater in patients with documented estrogen-sensitive disorders who received the agonist (75% vs. 20%, P < .05) CONCLUSION: Proximal tubal obstruction may be an estrogen-sensitive phenomenon in a subset of infertile patients. The administration of GnRH agonists may successfully overcome this state and result in enhanced conception rates.

Microendoscopy of the human fallopian tube.

Advances in fiberoptic technology make it possible to evaluate the tubal lumen endoscopically. Two basic procedures are salpingoscopy and falloposcopy. The former is a transfimbrial approach allowing visualization from the ampullary-isthmic junction to the fimbriae. The latter is a transcervical approach allowing assessment of the tubal lumen from the uterotubal ostium to the fimbriae. Both may be performed without general anesthesia. The procedures provide more sensitive information than laparoscopy with chromotubation or hysterosalpingography alone. Findings provide a strong correlation with conception. Technical shortcomings make falloposcopy more difficult than the more straightforward transfimbrial technique. With more widespread acceptance, endoscopic evaluation of the fallopian tube may become a standard component of the infertility evaluation.

Falloposcopy.

The role of the human fallopian tube in reproduction is more than a passive conduit. This organ is involved in oocyte pick-up, fertilization, and embryo transport. Metabolic substrates, cytokines, and immunoglobulins have been identified within the tubal lumen. Complex and coordinated endocrine secretions, neuromuscular activity, and cilial action are required for successful tubal function.

Add-back therapy and gonadotropin-releasing hormone agonists in the treatment of patients with endometriosis: can a consensus be reached? Add-Back Consensus Working Group.

OBJECTIVE: To reach a consensus on the role of add-back therapy for patients with endometriosis administered GnRH agonists (GnRH-a). DESIGN: Results of consensus conference reviewing MEDLINE search of English language abstracts of both prospective and retrospective series. SETTING: Consensus conference of 31 specialists in gynecologic surgery and reproductive endocrinology. PATIENT(S): Patients with symptomatic endometriosis who were candidates for GnRH-a therapy in treatment courses ranging in duration from 6 to 12 months. INTERVENTION(S): Oral steroidal and nonsteroidal add-back regimens. MAIN OUTCOME MEASURE(S): Alteration in painful symptoms, extent of disease, vasomotor symptoms, bone mineral density, and serum lipid profile. RESULT(S): When added to GnRH-a for 6 months, both 2.5 mg of norethindrone and 0.625 mg of conjugated equine estrogens with 5 mg/d of medroxyprogesterone acetate provide effective relief of vasomotor symptoms and decrease but do not eliminate bone mineral density loss. During 12 months of GnRH-a therapy, bone mineral density loss is eliminated effectively with an add-back of 5 mg of norethindrone acetate alone or in conjunction with low-dose conjugated equine estrogens. Organic bisphosphonates also may play a role. CONCLUSION(S): In patients with symptomatic endometriosis, the efficacy of GnRH agonists may be preserved and therapy prolonged while overcoming hypoestrogenic side effects with the use of appropriate add-back regimens.

Is intracytoplasmic sperm injection necessary for couples undergoing in vitro fertilization-embryo transfer with normal semen analyses but failing hamster egg penetration assays?

PURPOSE: Our purpose was to assess whether in vitro fertilization (IVF)-embryo transfer (ET) candidate couples with basically normal semen analyses but failing zona-free hamster egg penetration assay (HEPA) scores benefit from intracytoplasmic sperm injection (ICSI). METHODS: Twenty consecutive IVF candidate couples with normal-borderline semen analyses and failing HEPA scores were recruited. Mature oocytes obtained from each woman were randomly divided between ICSI (group I; n = 126 oocytes) and standard insemination techniques (group II; 138 oocytes). Fertilization (two pronuclei) and cleavage (2-4 cells) rates were assessed for both groups. RESULTS: There were no statistically significant differences between the two groups with respect to (mean +/- standard error of the mean) fertilization (group I, 63.1 +/- 7.75; group II, 77.8 +/- 4.7%) or cleavage (group I, 87.3 +/- 2.4%; group II, 91.2 +/- 3.5%) rates. CONCLUSIONS: ICSI is not beneficial for IVF-ET when sperm samples demonstrate a failing HEPA score but have normal or minimally compromised semen analysis parameters.

Historical prospective cohort study of the recurrence of pain after discontinuation of treatment with danazol or a gonadotropin-releasing hormone agonist.

OBJECTIVE: To determine the duration of time to the recurrence of pain attributable to endometriosis after the discontinuation of treatment with danazol or a GnRH agonist (GnRH-a) in patients who have had a satisfactory response to the treatment. DESIGN: Retrospective study. SETTING: Nine academic medical centers in three countries. PATIENT(S): Three hundred twenty-seven women with diagnosed and staged endometriosis who were treated with at least 6 months of danazol or a GnRH-a and who experienced significant pain relief with therapy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Duration of pain relief after completion of treatment as determined by a patient-initiated report of pain recurrence or increase in pain severity requiring intervention. RESULT(S): The median time to the recurrence of pain was 6.1 months for patients treated with danazol and 5.2 months for patients treated with a GnRH-a. CONCLUSION(S): Although there was a lack of uniformity in treatment effects across sites, the analyses have taken into account major covariant effects. The time to the recurrence of endometriosis-associated pain after danazol treatment was slightly longer than that after GnRH-a treatment.

Add-back therapy: extending safety and efficacy of GnRH analogues in the gynecologic patient.

GnRH analogues have been demonstrated to be effective medical therapy for symptomatic endometriosis. The use of these agents has been limited to 6 months due to hypoestrogenic side effects. A variety of steroidal and nonsteroidal add-back regimens have been used in an effort to eliminate such side effects while maintaining efficacy in order to enhance compliance, safety and duration such side effects while maintaining efficacy in order to enhance compliance, safety and duration of administration of these agents. Only 3 regimens have been shown to be efficacious in prolonging analogue use beyond 6 months by reducing vasomotor symptoms as well as preventing significant bone mineral density loss. These include daily norethindrone acetate 5 mg alone or in conjunction with conjugated equine estrogens 0.625 mg daily, as well as norethindrone 2.5 mg daily in conjunction with an organic bisphosphonate. With further investigation, such regimens may allow safe prolongation of GnRH analogue use without sacrificing efficacy in those endometriosis patients with severe pelvic pain.

Clinical and endocrine effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization.

OBJECTIVE: To assess the endocrine and clinical responses to microdose GnRH agonist (GnRH-a) that was administered in the early follicular phase before controlled ovarian hyperstimulation to poor responders who were candidates for IVF-ET. DESIGN: Prospective nonrandomized trial with historical controls. SETTING: Tertiary care university-affiliated infertility practice. PATIENT(S): Thirty-four IVF-ET candidates with a prior poor response to a standard long-protocol GnRH-a controlled ovarian hyperstimulation regimen (cycle A). Patients were divided into two groups based on their age at the initiation of cycle A (Group 1: < or = 39 years, n = 15; Group 2: > or = 40 years, n = 19). INTERVENTION(S): Low-dose oral contraceptive (x 21 d) followed by GnRH-a (leuprolide acetate; 40 micrograms s.c. b.i.d.) flare and urofollitropin initiated on day 3 of GnRH-a administration (cycle B). MAIN OUTCOME MEASURE(S): Comparative analysis of clinical responses (total urofollitropin dose used and number of oocytes retrieved as well as fertilization and clinical and ongoing pregnancy rates) and endocrine responses (serum E2, FSH, LH, T, and P levels) between cycles A and B in the two groups. Early follicular phase serum E2 and FSH changes in groups 1 and 2 were compared with changes in nine normal responder controls who were receiving a standard long-protocol GnRH-a/urofollitropin regimen (group 3). RESULT(S): Maximal E2 levels as well as clinical and ongoing pregnancy rates were higher in cycle B patients receiving microdose GnRH-a. Cancellation rates in cycle B were lower than in cycle A. Statistically significant increases in treatment day 6 serum FSH levels were noted during cycle B in both groups 1 and 2 but not in group 3 controls. No abnormal rises in LH, P, or T were noted in any of the groups. CONCLUSION(S): Microdose GnRH-a enhances urofollitropin response and clinical outcome in poor responders undergoing IVF-ET. This may be due to enhanced release of early follicular phase endogenous FSH without concomitant deleterious rises in androgen levels or corpus luteum rescue.

Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group.

OBJECTIVE: To evaluate the efficacy and safety of a GnRH agonist, leuprolide acetate depot, alone and in combination with three hormonal add-back regimens in the management of endometriosis-associated pelvic pain. METHODS: Two hundred and one patients were enrolled in this multicenter, randomized, double-blind, 1-year trial. All patients were given an intramuscular injection of leuprolide acetate depot 3.75 mg every 4 weeks. Patients were assigned to one of four treatment groups: Group A received placebos for progestin and estrogen, group B received norethindrone acetate 5 mg daily and placebo for estrogen, group C received norethindrone acetate 5 mg and conjugated equine estrogens 0.625 mg daily, and group D received norethindrone acetate 5 mg and conjugated equine estrogens 1.25 mg daily. Pelvic pain scores were assessed monthly, and bone density was measured after 24 and 52 weeks. RESULTS: By week 8, all four groups showed significant improvement in pelvic pain scores compared with baseline levels. A higher proportion of group D patients terminated the study prematurely due to a lack of improvement in symptoms. Group A experienced a 6.3 +/- 2.3% (P < or = .001) loss in bone density after 52 weeks of treatment, whereas bone density was preserved in all three add-back groups. CONCLUSION: The use of leuprolide acetate depot in combination with norethindrone acetate 5 mg alone, or with norethindrone acetate and conjugated equine estrogens 0.625 mg, provides effective suppression of pelvic pain symptoms associated with endometriosis while protecting against bone loss.

Incomplete androgen and progesterone suppression following midluteal GnRHa prior to controlled ovarian hyperstimulation for IVF-ET.

PURPOSE: We aimed to determine if midluteal GnRH agonist (GnRHa) use prior to controlled ovarian hyperstimulation (COH) results in uniform progesterone and androgen suppression and whether elevations of these hormones occurring early in follicular development may adversely effect the outcome of IVF-ET. METHODS: Forty-four COH cycles using midluteal GnRHa were evaluated. Serum gonadotropins (LH and FSH) and gonadal steroids (E2, A, P4, and T) were measured after 10 days of GnRHa administration [cycle day 31 (CD 31)] and again on the day of hCG administration, following COH. Cycle outcomes evaluated were the number of oocytes retrieved, morphologic grade, fertilization, implantation, pregnancy, and spontaneous abortion rates. RESULTS: Endogenous serum FSH was uniformly suppressed (6.32 +/- 0.47 IU/L) on CD 31, however, LH was not (23.76 +/- 0.76 IU/L). Five and four tenths percent of cycles demonstrated low-level P4 elevations (> or = 0.9 ng/ml), 24.4% demonstrated serum androstenedione levels > or = 600 pg/ml, and 39% of cycles were characterized by serum T levels > or = 200 pg/ml despite evidence of E2 suppression (< or = 30 pg/ml) and the absence of follicular growth by sonography. LH levels were not predictive of incomplete P4 or androgen suppression. Elevations of either P4, A, or T occurring early in the follicular phase were not found to correlate with an impairment in clinical cycle outcome. CONCLUSIONS: Midluteal GnRHa use prior to COH may result in incomplete suppression of circulating progresterone and androgens. However, these relative elevations, occurring early in the development of the follicular cohort, did not appear to affect IVF cycle outcome adversely.

Multicenter feasibility study of a new coaxial falloposcopy system.

We compared falloposcopy employing a new coaxial system with traditional laparoscopic chromotubation and hysterosalpingography in a prospective, multicenter clinical trial at five tertiary infertility centers. Based on findings at hysterosalpingography or laparoscopic chromotubation, the 16 women (22 tubes) in group 1 had a presumed diagnosis of proximal tubal obstruction, and the 4 (7 tubes) in group 2 had unexplained infertility. Cannulation was successfully achieved in 83.3% of tubes. In group 1, 85% (17/20) of visualized tubes were patent and 35% (7/20) were normal. In group 2, 40% (2/5) of visualized tubes were abnormal. Management was changed in 52.4% of women as a result of falloposcopic findings. Falloposcopy with this new coaxial system allows improved visualization with less bulky and less traumatic instruments. The system provides valuable information regarding the fallopian tube lumen that correlates poorly with that obtained with more traditional techniques.

An economically rational method of managing early-stage endometriosis.

Endometriosis is a common gynecologic disease among women of reproductive age. The lesions of early endometriosis may be missed during laparoscopy, which has been considered to be the definitive means of both diagnosis and treatment. Moreover, laparoscopic treatment of minimal-to-mild (stage 1 to 2) endometriosis does not always resolve associated chronic pelvic pain in many women. Instead, medical therapy with gonadotropin-releasing hormone (GnRH) agonists may be more effective in providing long-lasting pain relief in patients with similar disease stages. The author outlines the cost effectiveness of a trial course of GnRH agonists in women presenting with chronic pelvic pain.

Spontaneous pregnancies despite failed attempts at ovulation induction in a woman with latrogenic premature ovarian failure.

BACKGROUND: Women with premature ovarian failure may conceive spontaneously or following different regimens of ovulation induction. CASE: A 29-year-old woman with eight years of hypergonadotropic hypogonadism following chemotherapy and radiotherapy for Hodgkin's disease conceived spontaneously and spontaneously aborted after discontinuation of estrogen replacement. Subsequently she underwent pituitary gonadotrope downregulation and attempted controlled ovarian hyperstimulation without an ovarian response or follicular development. Despite this failure, she conceived spontaneously on two occasions, resulting in a live-born infant and an ongoing pregnancy. CONCLUSION: Cases of hypergonadotropic hypogonadism may not be permanent or irreversible. Interventional regimens may fail to induce ovulation despite the presence of residual oocytes capable of recruitment and fertilization.